Heterocyclic amide compounds having an RORvt inhibitory action

ABSTRACT

The present invention relates to compound (I) or a salt thereof which has a RORγt inhibitory action. In the formula (I), each symbol is as defined in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. application Ser. No. 16/576,293, filed onSep. 29, 2019, which is a divisional of U.S. application Ser. No.14/902,388, filed on Dec. 31, 2015, now U.S. Pat. No. 10,472,376, issuedon Nov. 12, 2019, which is a U.S. national stage entry of InternationalPatent Application No. PCT/JP2014/067649, filed on Jul. 2, 2014, whichclaims priority to Japanese Patent Application No. 2013-140213, filed onJul. 3, 2013, the entire contents of all of which are fully incorporatedherein by reference.

SEQUENCE LISTING

The text of the computer readable sequence listing filed herewith,titled “36015-303_Sequence_Listing_ST25”, created May 10, 2021, having afile size of 698 bytes, is hereby incorporated by reference in itsentirety.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound having an RORγtinhibitory action, a medicament containing the compound, and the like.

BACKGROUND OF THE INVENTION

Th17 cell and inflammatory cytokine (IL-17A, IL-17F, etc.) producedthereby cause a decrease in QOL as a severe etiology cell and factoraccompanying enhancement of a systemic new immune response, in variousautoimmune disease such as inflammatory bowel disease (IBD), rheumatoidarthritis, multiple sclerosis or psoriasis. However, the existingtherapeutic drugs show only limited effects, and therefore, the earliestpossible development of a novel therapeutic drug has been desired.

Involvement of T cells, inter alia, Th17 cell and inflammatory cytokines(IL-17A, IL-17F, etc.) produced thereby, in the pathology of theseimmune disease has been drawing attention in recent years.

Moreover, it has been recently clarified that a Retinoid-related OrphanReceptor (ROR) γt, which is one of the orphan nuclear receptors, playsan important role in the differentiation of Th17 cells and production ofIL-17A/IL-17F. That is, it has been reported that RORγt is mainlyexpressed in Th17 cells and functions as a transcription factor ofIL-17A and IL-17F, as well as a master regulator of Th17 celldifferentiation.

Therefore, a medicament that inhibits the action of RORγt is expected toshow a treatment effect on various immune disease by suppressingdifferentiation and activation of Th17 cells.

Non-Patent Document 1 discloses the following compound as an amidecompound.

Patent Document 1 discloses a compound represented by the formula:

which is a compound having a Xa factor inhibitory action, and is usefulfor the treatment of thromboembolism.

Patent Document 2 discloses a compound represented by the generalformula:

whereinE and F are independently a saturated or unsaturated non-cyclichydrocarbon group having 1, 2, 3, 4 or 5 carbon atoms;X and Y are independently methylene or the like;R₈ is hydrogen or the like; andA and B are the same or different and each is selected from

-   -   wherein R1, R2 and R3 are the same or different and each is        selected from hydrogen, halogen, an alkyl group having 1 to 5        carbon atoms, and the like,        which is a melanocortin receptor agonist or antagonist, and is        useful for the treatment of inflammation and the like.

Patent Document 3 discloses a compound represented by the formula:

whereinM* is (CH₂)_(n), (n=0, 1 or 2);P* is C═O, CONH, CO₂, —CH₂— or the like;A* is carbonyl(C═O) or the like;R is selected from H, alkyl (C₁-C₄) and the like;R¹ is selected from H, alkyl (C₁-C₄) and the like;R² is selected from H, alkyl (C₁-C₄) and the like;W is selected from (alpha-aminoacyl)amide, aminoalkyl, amino and thelike; andX is selected from aryl (C₆-C₁₀), mono-substituted aryl (C₆-C₁₀) and thelike,which is an efflux pump inhibitor, and is useful for the treatment ofbacterial infection.

Patent Document 4 discloses, as a fused heterocyclic compound, acompound represented by the formula:

whereinR^(1A) is an optionally substituted hydrocarbon group or an optionallysubstituted hydrocarbon-oxy group,R^(2A) and R^(3A) are each independently a hydrogen atom, an optionallysubstituted hydrocarbon group or the like, orR^(2A) and R^(3A) in combination optionally form, together with thecarbon atoms which they are bonded to, an optionally substitutedhydrocarbon ring,R^(5A) is a hydrogen atom or a halogen atom,Q′ is

-   -   wherein    -   [A¹] are the same or different and each is a methylene group        optionally substituted by C₁₋₆ alkyl group(s) optionally        substituted by hydroxy group(s) and the like, wherein the two        substituents bonded to the single carbon atom are optionally        combined to each other to form a hydrocarbon ring, and    -   n is an integer of 1 to 5, or the like, and        Ring B′ is a benzene ring optionally further having        substituent(s), or the like,        which has a RORγt inhibitory action, and is useful for the        treatment of inflammatory bowel disease (IBD) and the like.

Patent Document 5 discloses a compound represented by the formula:

wherein

-   -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a        substituent, or a nitrogen atom,    -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a        substituent, or a nitrogen atom,    -   A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a        substituent, or a nitrogen atom, or,    -   provided that when A² is CR^(A2) wherein R^(A2) is a        substituent, and    -   A³ is CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and        R^(A3) in combination optionally form, together with the carbon        atoms which they are bonded to, a carbocycle or a heterocycle,    -   R¹ is an optionally substituted carbocyclic group or the like,    -   R² is a hydrogen atom or a substituent,    -   one of R³ or R⁴ is an optionally substituted carbocyclic group,        an optionally substituted aromatic nitrogen-containing        heterocyclic group or an optionally substituted fused        non-aromatic heterocyclic group, and the other is a hydrogen        atom or a substituent,    -   R⁵ is a hydrogen atom or a substituent, and    -   R⁹ is a hydrogen atom or a hydroxy group, provided that when R⁹        is a hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and        CR^(A3), respectively.

Patent Document 6 discloses a compound represented by the formula:

wherein

-   -   X is carbon or nitrogen,    -   R¹ is —CF₂R^(a), wherein R^(a) is H, F or C₁₋₆ alkyl,    -   R² is H, halo, CF₃, a C₁₋₆ alkyl or C₁₋₃ alkoxy,    -   R³ is a chemical moiety selected from the group consisting of        C₃₋₆ cycloalkyl, 5- to 6-membered heterocycle, 5- to 6-membered        heteroaryl and phenyl, wherein the heterocycle and heteroaryl        each independently contains 1 to 3 heteroatoms selected from N,        O and S, and the moiety is each independently optionally        substituted by 1 to 3 substituents selected from halo, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃ and cyano,    -   R⁴ is H or C₁₋₆ alkyl, and    -   R⁵ is a chemical moiety selected from the group consisting of 5-        to 6-membered heteroaryl and quinolinyl, wherein the heteroaryl        each independently contains 1 to 3 heteroatoms selected from N,        O and S, and the moiety is each independently optionally        substituted by 1 to 3 of R⁶ substituents selected from C₁₋₆        alkyl, CF₃, cyano, C₁₋₆ alkoxy, halo, amino, C₁₋₃ alkylamino,        di-C₁₋₃ alkylamino, —CH₂P(O)(OR⁷)(OR⁸), —C(O)OR⁷, —CH₂C(O)OR⁷        and aryl C₁₋₆ alkyl, and R⁷ and R⁸ are each independently H or        C₁₋₆ alkyl, and the aryl of the arylalkyl is each independently        optionally substituted by 1 to 3 substituents selected from C₁₋₆        alkyl, CF₃, cyano, C₁₋₆ alkoxy, halo, carboxy, amino, C₁₋₃        alkylamino and di-C₁₋₃ alkylamino, which is useful for the        treatment of glucokinase activation-related diseases.

Non-Patent Document 2 discloses the following compound.

Patent Document 7 discloses a compound represented by the formula:

wherein each symbol is as defined in the document, which is useful forthe treatment or prophylaxis of cancer, cell signaling pathway-relateddiseases and microorganism infection-related diseases.

Patent Document 8 discloses a compound represented by the formula:

wherein

-   -   Q is a group represented by —C(—R11)=C(—R12)-SO₂— wherein R11        and R12 are bonded to each other to form a 5- to 7-membered ring        together with —C═C—, or each independently a hydrogen atom or a        substituent,    -   R1 is a substituent,    -   R2 is a substituent,    -   m is an integer of 0 to 5, when m is 2 or more, then plural R2        are the same or different, or they are optionally bonded to each        other to form a ring, and    -   X is a group capable of being leaved by coupling reaction with        an oxidized product of a developing agent.    -   Patent Document 9 discloses a compound represented by the        formula:

-   -   wherein    -   R¹, R², R³ and R⁴ are independently selected from hydrogen; C₁₋₃        alkyl; 3- to 8-membered monocyclic or bicyclic cycloalkyl; 3- to        8-membered monocyclic or bicyclic heterocycle wherein one, two        or three carbon atoms are replaced by heteroatom(s) selected        from oxygen, nitrogen and sulfur; 6- to 10-membered monocyclic        or bicyclic aryl; or 5- to 10-membered monocyclic or bicyclic        heteroaryl wherein one, two, three or four carbon atoms are        optionally replaced by nitrogen, oxygen or sulfur; the all of        groups are optionally unsubstituted or substituted by 1 or        plural substituents;    -   X is —N— or —O—;    -   R⁵ is —H or —F;    -   R⁶ is —H or —CH₃; or    -   when X is —N—, and R³ and R⁴ in combination form a 4- to        6-membered heterocycle together with the nitrogen atom they are        bonded to, then one additional carbon atom may be replaced by        nitrogen, oxygen or sulfur,    -   which is useful for the treatment of cancer.

The following compounds are registered Chemical Abstracts.

CAS Registry Number: 1427736-73-9

CAS Registry Number: 1323260-38-3

CAS Registry Number: 1323005-31-7

CAS Registry Number: 1316015-84-5

CAS Registry Number: 1286063-95-3

CAS Registry Number: 1277664-46-6

CAS Registry Number: 1217860-74-6

CAS Registry Number: 1217709-83-5

CAS Registry Number: 957036-06-5

CAS Registry Number: 956728-16-8

DOCUMENT LIST Patent Document

-   [Patent Document 1] WO 2004/108892-   [Patent Document 2] WO 2001/055106-   [Patent Document 3] WO 99/37667-   [Patent Document 4] WO 2013/042782-   [Patent Document 5] WO 2013/100027-   [Patent Document 6] WO 2010/013161-   [Patent Document 7] FR 2860793-   [Patent Document 8] EP 1341035-   [Patent Document 9] WO 2009/095324

Non-Patent Document

-   [Non-Patent Document 1] Journal of Combinatorial Chemistry (2010),    12(4), 414-416-   [Non-Patent Document 2] Bioorganic & Medicinal Chemistry Letters    (2009), 19(12), 3247-3252

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention aims to provide a compound having a superior RORγtinhibitory action, and is useful as an agent for the prophylaxis ortreatment of psoriasis, inflammatory bowel disease (IBD), ulcerativecolitis (UC), Crohn's disease (CD), rheumatoid arthritis, multiplesclerosis, uveitis, asthma, ankylopoietic spondylarthritis, systemiclupus erythematosus (SLE) and the like.

Means of Solving the Problems

The present inventors have found that a compound represented by thefollowing formula (I) or a salt thereof has a superior RORγt inhibitoryaction based on the specific chemical structure thereof and affordssuperior efficacy as an agent for the prophylaxis or treatment ofpsoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC),Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis, uveitis,asthma, ankylopoietic spondylarthritis, systemic lupus erythematosus(SLE) and the like. The present inventors have conducted intensivestudies based on the finding and completed the present invention.

Accordingly, the present invention relates to the followings.

[1] A compound represented by the following formula (I):

whereinRing A is an optionally further substituted 6-membered aromatic ring,R¹ is

-   -   (1) a group represented by the formula:        -Q(R^(1a))(R^(1b))(R^(1c)) wherein        -   Q is a carbon atom, a silicon atom or a germanium atom, and        -   R^(1a), R^(1b) and R^(1c) are each independently a            substituent, or        -   R^(1a) and R^(1b) in combination optionally form, together            with the adjacent Q, an optionally substituted ring,    -   (2) a neopentyl group, or    -   (3) a trimethylsilylmethyl group,        R² is    -   (1) a group represented by the formula:

-   -   -   wherein        -   R⁵ is an optionally substituted alkyl group or an optionally            substituted alkoxy group, and        -   the benzene ring in the formula optionally has additional            substituent (s) besides R⁵,

    -   (2) an optionally substituted bicyclic fused heterocyclic group,        or

    -   (3) a group represented by the formula: -L-Z¹        -   wherein        -   L is a bond or CH₂, and Z¹ is an optionally substituted            non-aromatic ring group,            R³ is a hydrogen atom or a substituent, and            R⁴ is a substituent (provided that

    -   (1) a group represented by the formula:

-   -   wherein    -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a        substituent, or a nitrogen atom,    -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a        substituent, or a nitrogen atom,        -   A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a            substituent, or a nitrogen atom, or        -   when A² is CR^(A2) wherein R^(A2) is a substituent, and A³            is CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and            R^(A3) in combination optionally form, together with the            carbon atoms that they are bonded to, a hydrocarbon ring or            a heterocycle,        -   R⁹ is a hydrogen atom or a hydroxy group, and when R⁹ is a            hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and            CR^(A), respectively, and        -   R¹⁰ is a hydroxy group or an optionally substituted C₁₋₆            alkoxy group, and    -   (2) an optionally substituted C₁₋₆ alkoxy group are excluded),        or        when R³ is a substituent, then R³ and R⁴ in combination        optionally form, together with the nitrogen atom adjacent to R³        and the carbon atom adjacent to R⁴, an optionally substituted        ring (provided that    -   (1) a cyclic group represented by the formula:

-   -   -   wherein X is CH or a nitrogen atom, which is optionally            further substituted, and

    -   (2) a cyclic group represented by the formula:

-   -   -   are excluded), and            the substituents that the ring optionally has optionally            form a spiro ring,            provided that

-   5-chloro-N-[1-cyclohexyl-2-oxo-2-[[4-[1-(1-pyrrolidinylmethyl)cyclopropyl]phenyl]amino]ethyl]-2-thiophenecarboxamide,

-   α-(acetylamino)-N-[4-(trifluoromethyl)phenyl]-cyclopentaneacetamide,

-   α-(acetylamino)-N-[4-(1,1-dimethylethyl)phenyl]-cyclopentaneacetamide,

-   α-(acetylamino)-N-[2-bromo-4-(trifluoromethyl)phenyl]-cyclopentaneacetamide,    and

-   N-(4-tert-butyl-2-((5-ethyl-2-(2-ethyl-4,4-dimethylpentyl)-7,7-dimethyloctyl)oxy)phenyl)-2-(5,5-dimethyl-2,4-dioxo-1,3-oxazolidin-3-yl)-2-(2-octadecyl-1,1-dioxido-2H-1,2,4-benzthiadiazin-3-yl)acetamide    are excluded,    or a salt thereof (hereinafter sometimes to be referred to as    compound (I)).    [2] The compound or salt of the above-mentioned [1], wherein the    substituent that Ring A optionally further has is a fluorine atom or    a chlorine atom.    [3] The compound or salt of the above-mentioned [1], wherein R¹ is a    tert-butyl group, a neopentyl group or a trimethylsilyl group.    [4] The compound or salt of the above-mentioned [1], wherein R² is    (1) a group represented by the formula:

wherein R⁵ is an alkoxy group or an alkoxyalkyl group,

(2) a tetrahydro-2H-pyran-4-yl group,

(3) a 4,4-difluorocyclohexyl group,

(4) a 1-methyl-1H-indazol-5-yl group, or

(5) a 2,3-dihydro-1-benzofuran-5-yl group.

[5] The compound or salt of the above-mentioned [1], wherein R³ is ahydrogen atom or a methyl group.

[6] The compound or salt of the above-mentioned [1], wherein R⁴ is (1)an optionally substituted 5-membered heterocyclic group, (2) anoptionally substituted 6-membered non-aromatic heterocyclic group, (3)an optionally substituted 4-membered non-aromatic heterocyclic group,(4) an optionally substituted C₃₋₄ cycloalkyl group, or (5) anoptionally substituted C₁₋₄ alkyl group.[7](3S)—N-((1R)-2-((4-tert-Butyl-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamideor a salt thereof.[8]N-((1R)-2-((3,5-Difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamideor a salt thereof.[9](2R)—N-(4-tert-Butyl-3,5-difluorophenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)-2-(1-methyl-1H-indazol-5-yl)acetamideor a salt thereof.[10] A medicament comprising the compound or salt of claim 1.[11] A medicament comprising a compound represented by the followingformula (I′):

whereinRing A is an optionally further substituted 6-membered aromatic ring,R¹ is(1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom, a silicon atom or a germanium atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently a substituent,        or    -   R^(1a) and R^(1b) in combination optionally form, together with        the adjacent Q, an optionally substituted ring,        (2) a neopentyl group, or        (3) a trimethylsilylmethyl group,        R² is        (1) a group represented by the formula:

-   -   wherein    -   R⁵ is an optionally substituted alkyl group or an optionally        substituted alkoxy group, and    -   the benzene ring in the formula optionally has additional        substituent(s) besides R⁷,        (2) an optionally substituted bicyclic fused heterocyclic group,        or        (3) a group represented by the formula: -L-Z¹    -   wherein    -   L is a bond or CH₂, and    -   Z¹ is an optionally substituted non-aromatic ring group,        R³ is a hydrogen atom or a substituent, and        R⁴ is a substituent (provided that    -   (1) a group represented by the formula:

-   -   -   wherein        -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A² is CR^(A3) wherein R^(A3) is a hydrogen atom or a            substituent, or a nitrogen atom, or        -   when A² is CR^(A2) wherein R^(A2) is a substituent, and A³            is CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and            R^(A3) in combination optionally form, together with the            carbon atoms that they are bonded to, a hydrocarbon ring or            a heterocycle,        -   R⁹ is a hydrogen atom or a hydroxy group, and when R⁹ is a            hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and            CR^(A), respectively, and        -   R¹⁰ is a hydroxy group or an optionally substituted C₁₋₆            alkoxy group, and

    -   (2) an optionally substituted C₁₋₆ alkoxy group are excluded),        or        when R³ is a substituent, then R³ and R⁴ in combination        optionally form, together with the nitrogen atom adjacent to R        and the carbon atom adjacent to R⁴, an optionally substituted        ring, and the substituents that the ring optionally has        optionally form a spiro ring,        or a salt thereof (hereinafter sometimes to be referred to as        compound (I′)), which is a RORγt inhibitor.        [12] A medicament comprising a compound represented by the        following formula (I′):

whereinRing A is an optionally further substituted 6-membered aromatic ring,R¹ is

-   -   (1) a group represented by the formula:        -Q(R^(1a))(R^(1b))(R^(1c))        -   wherein        -   Q is a carbon atom, a silicon atom or a germanium atom, and        -   R^(1a), R^(1b) and R^(1c) are each independently a            substituent, or R^(1a) and R^(1b) in combination optionally            form, together with the adjacent Q, an optionally            substituted ring,    -   (2) a neopentyl group, or    -   (3) a trimethylsilylmethyl group,        R² is    -   (1) a group represented by the formula:

-   -   -   wherein        -   R³ is an optionally substituted alkyl group or an optionally            substituted alkoxy group, and        -   the benzene ring in the formula optionally has additional            substituent(s) besides R⁵,

    -   (2) an optionally substituted bicyclic fused heterocyclic group,        or

    -   (3) a group represented by the formula: -L-Z¹        -   wherein        -   L is a bond or CH₂, and        -   Z¹ is an optionally substituted non-aromatic ring group,            R³ is a hydrogen atom or a substituent, and            R⁴ is a substituent (provided that

    -   (1) a group represented by the formula:

-   -   -   wherein        -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a            substituent, or a nitrogen atom, or        -   when A² is CR^(A2) wherein R^(A2) is a substituent, and A³            is CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and            R^(A3) in combination optionally form, together with the            carbon atoms that they are bonded to, a hydrocarbon ring or            a heterocycle,        -   R⁹ is a hydrogen atom or a hydroxy group, and when R⁹ is a            hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and            CR^(A), respectively, and        -   R¹⁰ is a hydroxy group or an optionally substituted C₁₋₆            alkoxy group, and

    -   (2) an optionally substituted C₁₋₆ alkoxy group are excluded),        or        when R³ is a substituent, then R³ and R⁴ in combination        optionally form, together with the nitrogen atom adjacent to R³        and the carbon atom adjacent to R⁴, an optionally substituted        ring, and the substituents that the ring optionally has        optionally form a spiro ring,        or a salt thereof, which is an agent for the prophylaxis or        treatment of psoriasis, inflammatory bowel disease (IBD),        ulcerative colitis (UC), Crohn's disease (CD), rheumatoid        arthritis, multiple sclerosis, uveitis, asthma, ankylopoietic        spondylarthritis or systemic lupus erythematosus (SLE).        [13] A method of inhibiting RORγt, which comprises administering        an effective amount of a compound represented by the following        formula (I′):

whereinRing A is an optionally further substituted 6-membered aromatic ring,R¹ is

-   -   (1) a group represented by the formula:        -Q(R^(1a))(R^(1b))(R^(1c))        -   wherein        -   Q is a carbon atom, a silicon atom or a germanium atom, and        -   R^(1a), R^(1b) and R^(1c) are each independently a            substituent, or R^(1a) and R^(1b) in combination optionally            form, together with the adjacent Q, an optionally            substituted ring,    -   (2) a neopentyl group, or    -   (3) a trimethylsilylmethyl group,        R¹ is    -   (1) a group represented by the formula:

-   -   -   wherein        -   R⁵ is an optionally substituted alkyl group or an optionally            substituted alkoxy group, and        -   the benzene ring in the formula optionally has additional            substituent(s) besides R⁵,

    -   (2) an optionally substituted bicyclic fused heterocyclic group,        or

    -   (3) a group represented by the formula: -L-Z¹        -   wherein        -   L is a bond or CH₂, and        -   Z¹ is an optionally substituted non-aromatic ring group,            R³ is a hydrogen atom or a substituent, and            R⁴ is a substituent (provided that

    -   (1) a group represented by the formula:

-   -   -   wherein        -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a            substituent, or a nitrogen atom, or        -   when A² is CR^(A2) wherein R^(A2) is a substituent, and A³            is CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and            R^(A3) in combination optionally form, together with the            carbon atoms that they are bonded to, a hydrocarbon ring or            a heterocycle,        -   R⁹ is a hydrogen atom or a hydroxy group, and when R⁹ is a            hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and            CR^(A), respectively, and        -   R¹⁰ is a hydroxy group or an optionally substituted C₁₋₆            alkoxy group, and

    -   (2) an optionally substituted C₁₋₆ alkoxy group are excluded),        or        when R³ is a substituent, then R³ and R⁴ in combination        optionally form, together with the nitrogen atom adjacent to R³        and the carbon atom adjacent to R⁴, an optionally substituted        ring, and the substituents that the ring optionally has        optionally form a spiro ring, or a salt thereof to a mammal.        [14] A method for the prophylaxis or treatment of psoriasis,        inflammatory bowel disease (IBD), ulcerative colitis (UC),        Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis,        uveitis, asthma, ankylopoietic spondylarthritis or systemic        lupus erythematosus (SLE), which comprises administering an        effective amount of a compound represented by the following        formula (I′):

whereinRing A is an optionally further substituted 6-membered aromatic ring,R¹ is

-   -   (1) a group represented by the formula:        -Q(R^(1a))(R^(1b))(R^(1c))        -   wherein        -   Q is a carbon atom, a silicon atom or a germanium atom, and        -   R^(1a), R^(1b) and R^(1c) are each independently a            substituent, or        -   R^(1a) and R^(1b) in combination optionally form, together            with the adjacent Q, an optionally substituted ring,    -   (2) a neopentyl group, or    -   (3) a trimethylsilylmethyl group,        R² is    -   (1) a group represented by the formula:

-   -   -   wherein        -   R⁵ is an optionally substituted alkyl group or an optionally            substituted alkoxy group, and the benzene ring in the            formula optionally has additional substituent (s) besides            R⁵,

    -   (2) an optionally substituted bicyclic fused heterocyclic group,        or

    -   (3) a group represented by the formula: -L-Z¹ wherein        -   L is a bond or CH₂, and        -   Z¹ is an optionally substituted non-aromatic ring group,            R³ is a hydrogen atom or a substituent, and            R⁴ is a substituent (provided that

    -   (1) a group represented by the formula:

-   -   -   wherein        -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a            substituent, or a nitrogen atom, or        -   when A² is CR^(A2) wherein R^(A2) is a substituent, and A³            is CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and            R^(A3) in combination optionally form, together with the            carbon atoms that they are bonded to, a hydrocarbon ring or            a heterocycle,        -   R⁹ is a hydrogen atom or a hydroxy group, and when R⁹ is a            hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and            CR^(A), respectively, and        -   R¹⁰ is a hydroxy group or an optionally substituted C₁₋₆            alkoxy group, and

    -   (2) an optionally substituted C₁₋₆ alkoxy group are excluded),        or        when R³ is a substituent, then R³ and R⁴ in combination        optionally form, together with the nitrogen atom adjacent to R³        and the carbon atom adjacent to R⁴, an optionally substituted        ring, and the substituents that the ring optionally has        optionally form a spiro ring,        or a salt thereof to a mammal.        [15] Use of a compound represented by the following formula        (I′):

whereinRing A is an optionally further substituted 6-membered aromatic ring,R¹ is

-   -   (1) a group represented by the formula:        -Q(R^(1a))(R^(1b))(R^(1c))        -   wherein        -   Q is a carbon atom, a silicon atom or a germanium atom, and        -   R^(1a), R^(1b) and R^(1c) are each independently a            substituent, or        -   R^(1a) and R^(1b) in combination optionally form, together            with the adjacent Q, an optionally substituted ring,    -   (2) a neopentyl group, or    -   (3) a trimethylsilylmethyl group,        R² is    -   (1) a group represented by the formula:

-   -   -   wherein        -   R⁵ is an optionally substituted alkyl group or an optionally            substituted alkoxy group, and        -   the benzene ring in the formula optionally has additional            substituent(s) besides R⁵,

    -   (2) an optionally substituted bicyclic fused heterocyclic group,        or

    -   (3) a group represented by the formula: -L-Z¹        -   wherein        -   L is a bond or CH₂, and        -   Z¹ is an optionally substituted non-aromatic ring group,            R³ is a hydrogen atom or a substituent, and            R⁴ is a substituent (provided that

    -   (1) a group represented by the formula:

-   -   -   wherein        -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a            substituent, or a nitrogen atom, or        -   when A² is CR^(A2) wherein R^(A2) is a substituent, and A³            is CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and            R^(A3) in combination optionally form, together with the            carbon atoms that they are bonded to, a hydrocarbon ring or            a heterocycle,        -   R⁹ is a hydrogen atom or a hydroxy group, and when R⁹ is a            hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and            CR^(A), respectively, and        -   R¹⁰ is a hydroxy group or an optionally substituted C₁₋₆            alkoxy group, and

    -   (2) an optionally substituted C₁₋₆ alkoxy group are excluded),        or        when R³ is a substituent, then R³ and R⁴ in combination        optionally form, together with the nitrogen atom adjacent to R³        and the carbon atom adjacent to R⁴, an optionally substituted        ring, and the substituents that the ring optionally has        optionally form a spiro ring,        or a salt thereof, for the production of an agent for the        prophylaxis or treatment of psoriasis, inflammatory bowel        disease (IBD), ulcerative colitis (UC), Crohn's disease (CD),        rheumatoid arthritis, multiple sclerosis, uveitis, asthma,        ankylopoietic spondylarthritis or systemic lupus erythematosus        (SLE).        [16] A compound represented by the following formula (I′):

whereinRing A is an optionally further substituted 6-membered aromatic ring,R¹ is

-   -   (1) a group represented by the formula:        -Q(R^(1a))(R^(1b))(R^(1c))        -   wherein        -   Q is a carbon atom, a silicon atom or a germanium atom, and        -   R^(1a), R^(1b) and R^(1c) are each independently a            substituent, or        -   R^(1a) and R^(1b) in combination optionally form, together            with the adjacent Q, an optionally substituted ring,    -   (2) a neopentyl group, or    -   (3) a trimethylsilylmethyl group,        R² is    -   (1) a group represented by the formula:

-   -   -   wherein        -   R⁵ is an optionally substituted alkyl group or an optionally            substituted alkoxy group, and        -   the benzene ring in the formula optionally has additional            substituent(s) besides R⁵,

    -   (2) an optionally substituted bicyclic fused heterocyclic group,        or

    -   (3) a group represented by the formula: -L-Z¹        -   wherein        -   L is a bond or CH₂, and        -   Z¹ is an optionally substituted non-aromatic ring group,            R³ is a hydrogen atom or a substituent, and            R⁴ is a substituent (provided that

    -   (1) a group represented by the formula:

-   -   -   wherein        -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a            substituent, or a nitrogen atom, or        -   when A² is CR^(A2) wherein R^(A2) is a substituent, and A³            is CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and            R^(A3) in combination optionally form, together with the            carbon atoms that they are bonded to, a hydrocarbon ring or            a heterocycle,        -   R⁹ is a hydrogen atom or a hydroxy group, and when R⁹ is a            hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and            CR^(A), respectively, and        -   R¹⁰ is a hydroxy group or an optionally substituted C₁₋₆            alkoxy group, and

    -   (2) an optionally substituted C₁₋₆ alkoxy group are excluded),        or        when R³ is a substituent, then R³ and R⁴ in combination        optionally form, together with the nitrogen atom adjacent to R³        and the carbon atom adjacent to R⁴, an optionally substituted        ring, and the substituents that the ring optionally has        optionally form a spiro ring,        or a salt thereof, for use in the prophylaxis or treatment of        psoriasis, inflammatory bowel disease (IBD), ulcerative colitis        (UC), Crohn's disease (CD), rheumatoid arthritis, multiple        sclerosis, uveitis, asthma, ankylopoietic spondylarthritis or        systemic lupus erythematosus (SLE).        [1′] A compound represented by the formula (I″):

whereinRing A is an optionally further substituted 6-membered aromatic ring,R¹ is

-   -   (1) a group represented by the formula:        -Q(R^(1a))(R^(1b))(R^(1c))        -   wherein        -   Q is a carbon atom, a silicon atom or a germanium atom, and        -   R^(1a), R^(1b) and R^(1c) are each independently a            substituent, or        -   R^(1a) and R^(1b) in combination optionally form, together            with the adjacent Q, an optionally substituted ring,    -   (2) a neopentyl group, or    -   (3) a trimethylsilylmethyl group,        R¹ is    -   (1) a group represented by the formula:

-   -   -   wherein        -   R⁵ is an optionally substituted alkyl group or an optionally            substituted alkoxy group, and        -   the benzene ring in the formula optionally has additional            substituent(s) besides R⁵,

    -   (2) an optionally substituted bicyclic fused heterocyclic group,        or

    -   (3) a group represented by the formula: -L-Z¹        -   wherein        -   L is a bond or CH₂, and        -   Z¹ is an optionally substituted non-aromatic ring group,            R³ is a hydrogen atom or a substituent, and            R⁴ is a substituent (provided that a group represented by            the formula:

-   -   -   wherein        -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a            substituent, or a nitrogen atom, or        -   when A² is CR^(A2) wherein R^(A2) is a substituent, and A³            is CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and            R^(A3) in combination optionally form, together with the            carbon atoms that they are bonded to, a hydrocarbon ring or            a heterocycle, and        -   R⁹ is a hydrogen atom or a hydroxy group, and when R⁹ is a            hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and            CR^(A), respectively,        -   is excluded), or            when R³ is a substituent, then R³ and R⁴ in combination            optionally form, together with the nitrogen atom adjacent to            R³ and the carbon atom adjacent to R⁴, an optionally            substituted ring,            provided that

-   5-chloro-N-[1-cyclohexyl-2-oxo-2-[[4-[1-(1-pyrrolidinylmethyl)cyclopropyl]phenyl]amino]ethyl]-2-thiophenecarboxamide,

-   α-(acetylamino)-N-[4-(trifluoromethyl)phenyl]-cyclopentaneacetamide,

-   α-(acetylamino)-N-[4-(1,1-dimethylethyl)phenyl]-cyclopentaneacetamide,    and

-   α-(acetylamino)-N-[2-bromo-4-(trifluoromethyl)phenyl]-cyclopentaneacetamide    are excluded,    or a salt thereof (hereinafter sometimes to be referred to as    compound (I″)).    [2′] A compound represented by the formula (I″):

whereinRing A is an optionally further substituted 6-membered aromatic ring,R¹ is a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently a substituent,        or    -   R^(1a) and R^(1b) in combination optionally form, together with        the adjacent Q, an optionally substituted ring, or a neopentyl        group,        R² is    -   (1) a group represented by the formula:

-   -   -   wherein        -   R⁵ is an optionally substituted alkyl group or an optionally            substituted alkoxy group, and the benzene ring in the            formula optionally has additional substituent (s) besides            R⁵,

    -   (2) an optionally substituted bicyclic fused heterocyclic group,        or

    -   (3) a group represented by the formula: -L-Z¹        -   wherein        -   L is a bond or CH₂, and        -   Z¹ is an optionally substituted non-aromatic ring group,            R³ is a hydrogen atom or a substituent, and            R⁴ is a substituent (provided that a group represented by            the formula:

-   -   wherein    -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a        substituent, or a nitrogen atom,    -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a        substituent, or a nitrogen atom,    -   A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a        substituent, or a nitrogen atom, or    -   when A² is CR^(A2) wherein R^(A2) is a substituent, and A³ is        CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and R^(A3)        in combination optionally form, together with the carbon atoms        that they are bonded to, a hydrocarbon ring or a heterocycle,        and    -   R⁹ is a hydrogen atom or a hydroxy group, and when R⁹ is a        hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and        CR^(A), respectively,    -   is excluded), or provided that

-   5-chloro-N-[1-cyclohexyl-2-oxo-2-[[4-[1-(1-pyrrolidinylmethyl)cyclopropyl]phenyl]amino]ethyl]-2-thiophenecarboxamide    or a salt thereof,

-   α-(acetylamino)-N-[4-(trifluoromethyl)phenyl]-cyclopentaneacetamide    or a salt thereof,

-   α-(acetylamino)-N-[4-(1,1-dimethylethyl)phenyl]-cyclopentaneacetamide    or a salt thereof, and

-   α-(acetylamino)-N-[2-bromo-4-(trifluoromethyl)phenyl]-cyclopentaneacetamide    or a salt thereof,    are excluded,    or a salt thereof.    [3′] A medicament comprising the compound or salt of the    above-mentioned [1′] or [2′].    [4′] The medicament of the above-mentioned [3′], which is a RORγt    inhibitor.    [5′] The medicament of the above-mentioned [3′], which is an agent    for the prophylaxis or treatment of inflammatory bowel disease    (IBD), ulcerative colitis (UC), Crohn's disease (CD), rheumatoid    arthritis, multiple sclerosis or psoriasis.

Effect of the Invention

The compound of the present invention has a superior RORγt inhibitoryaction, and is useful as an agent for the prophylaxis or treatment ofpsoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC),Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis, uveitis,asthma, ankylopoietic spondylarthritis, systemic lupus erythematosus(SLE) and the like.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is explained in detail in the following.

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, a halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, a halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, a halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, a halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, a halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, a halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following Substituent Group A.

[Substituent Group A]

(1) a halogen atom,

(2) a nitro group,

(3) a cyano group,

(4) an oxo group,

(5) a hydroxy group,

(6) an optionally halogenated C₁₋₆ alkoxy group,

(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),

(8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),

(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),

(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),

(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),

(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),

(13) a C₁₋₁₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),

(14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),

(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),

(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),

(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),

(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethylsulfonyloxy),

(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),

(20) an optionally halogenated C₁₋₆ alkylthio group,

(21) a 5- to 14-membered aromatic heterocyclic group,

(22) a 3- to 14-membered non-aromatic heterocyclic group,

(23) a formyl group,

(24) a carboxy group,

(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,

(26) a C₆₋₁₄ aryl-carbonyl group,

(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,

(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,

(29) a C₁₋₆ alkoxy-carbonyl group,

(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),

(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),

(32) a carbamoyl group,

(33) a thiocarbamoyl group,

(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,

(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),

(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),

(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),

(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,

(39) a C₆₋₁₄ arylsulfonyl group,

(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group

(e.g., pyridylsulfonyl, thienylsulfonyl),

(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,

(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),

(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),

(44) an amino group,

(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),

(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),

(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),

(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),

(49) a formylamino group,

(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),

(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl) an amino group (e.g.,N-acetyl-N-methylamino),

(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),

(53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),

(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),

(55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino),

(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),

(57) an optionally halogenated C₁₋₆ alkyl group,

(58) a C₂₋₆ alkenyl group,

(59) a C₂₋₆ alkynyl group,

(60) a C₃₋₁₀ cycloalkyl group,

(61) a C₃₋₁₀ cycloalkenyl group, and

(62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9- to 14-membered fused polycyclic (preferably bi ortricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the above-mentioned Substituent Group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from SubstituentGroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl) an aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl) an amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl) an aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl) an amino group (e.g., N-acetyl-N-methylamino) anda (C₁₋₆ alkyl) (C₆₋₁₄ aryl-carbonyl) an amino group (e.g.,N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent Group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₅₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent Group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromSubstituent Group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxyl group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from SubstituentGroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from Substituent Group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₅ aralkyl group,each of which optionally has 1 to 3 substituents selected fromSubstituent Group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

In the present specification, examples of the “C₁₋₆ alkylene group”include —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—,—CH(CH₃)—, —C(CH₃)₂—, —CH(C₂H₅)—, —CH(C₃H₇)—, —CH(CH(CH₃)₂)—,—(CH(CH₃))₂—, —CH₂—CH(CH₃)—, —CH(CH₃)—CH₂—, —CH₂—CH₂—C(CH₃)₂—,—C(CH₃)₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—C(CH₃)₂— and —C(CH₃)₂—CH₂—CH₂—CH₂—.

In the present specification, examples of the “C₂₋₆ alkenylene group”include —CH═CH—, —CH₂—CH═CH—, —CH═CH—CH₂—, —C(CH₃)₂—CH═CH—,—CH═CH—C(CH₃)₂—, —CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—, —CH═CH—CH₂—CH₂—,—CH═CH—CH═CH—, —CH═CH—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH═CH—.

In the present specification, examples of the “C₂₋₆ alkynylene group”include —C≡C—, —CH₂—C≡C—, —C≡C—CH₂—, —C(CH₃)₂—C≡C—, —C≡C—C(CH₃)₂—,—CH₂—C≡C—CH₂—, —CH₂—CH₂—C≡C—, —C≡C—CH₂—CH₂—, —C≡C—C≡C—,—C≡C—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—C≡C—.

The definition of each symbol in the formulas (I), (I′) and (I″) isexplained in detail in the following.

Ring A is an optionally further substituted 6-membered aromatic ring.

Examples of the “6-membered aromatic ring” of the “optionally furthersubstituted 6-membered aromatic ring” represented by Ring A include abenzene ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, apyrazine ring and a triazine ring. Among them, a benzene ring ispreferable.

The “6-membered aromatic ring” is optionally further substituted, forexample, by substituent(s) selected from the above-mentioned SubstituentGroup A. The number of the substituents is, for example, 1 to 3. Whenthe number of the substituents is 2 or more, the respective substituentsmay be the same or different.

Examples of the substituent that the “6-membered aromatic ring”optionally further has are preferably (1) a halogen atom (e.g., afluorine atom, a chlorine atom) and (2) a cyano group; more preferably ahalogen atom; further more preferably a fluorine atom and a chlorineatom; particularly preferably a fluorine atom.

Ring A is preferably a 6-membered aromatic ring (preferably a benzenering) optionally further substituted by 1 to 3 substituents selectedfrom

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (2) a cyano group.

Ring A is more preferably a benzene ring optionally further substitutedby 1 to 3 substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (2) a cyano group.

Ring A is further more preferably a benzene ring optionally furthersubstituted by 1 to 3 halogen atoms (e.g., a fluorine atom).

R¹ is

-   (1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   Q is a carbon atom, a silicon atom or a germanium atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently a substituent,        or    -   R^(1a) and R^(1b) in combination optionally form, together with        the adjacent Q, an optionally substituted ring,-   (2) a neopentyl group, or-   (3) a trimethylsilylmethyl group.

Examples of the “optionally substituted ring” formed by R^(1a) andR^(1b) in combination together with the adjacent Q include a C₃₋₁₀cycloalkane ring, a C₃₋₁₀ cycloalkene ring and a non-aromaticheterocycle, each of which is optionally substituted by substituent(s)selected from the above-mentioned Substituent Group A.

Examples of the “C₃₋₁₀ cycloalkane ring” exemplified as the “optionallysubstituted ring” formed by R^(1a) and R^(1b) in combination togetherwith the adjacent Q include a ring corresponding to the above-mentioned“C₃₋₁₀ cycloalkyl group”.

Examples of the “C₃₋₁₀ cycloalkene ring” exemplified as the “optionallysubstituted ring” formed by R^(1a) and R^(1b) in combination togetherwith the adjacent Q include a ring corresponding to the above-mentioned“C₃₋₁₀ cycloalkenyl group”.

Examples of the “non-aromatic heterocycle” exemplified as the“optionally substituted ring” formed by R^(1a) and R^(1b) in combinationtogether with the adjacent Q include a ring corresponding to theabove-mentioned “non-aromatic heterocyclic group”.

The number of the substituents in the “optionally substituted ring” is,for example, 1 to 3. When the number of the substituents is 2 or more,the respective substituents may be the same or different.

R^(1a), R^(1b) and R^(1c) in the formula: -Q(R^(1a))(R^(1b))(R^(1c)) areeach preferably neither a cyclic group, nor a group substituted bycyclic group(s).

Examples of the “cyclic group” in R^(1a), R^(1b) and R^(1c) include theabove-mentioned “C₃₋₁₀ cycloalkyl group”, “C₃₋₁₀ cycloalkenyl group”,“C₆₋₁₄ aryl group” and “heterocyclic group”.

R¹ is preferably

-   (1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   Q is a carbon atom, a silicon atom or a germanium atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (b) a hydroxy group,    -   (c) a C₆₋₁₄ aryl group (e.g., phenyl),    -   (d) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (e) a cyano group,    -   (f) a carbamoyl group optionally mono- or di-substituted by        C₃₋₁₀ cycloalkyl group(s) (e.g., cyclopropyl), or    -   (g) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or        R^(1a) and R^(1b) in combination form, together with the        adjacent Q, a C₁₋₁₀ cycloalkane ring (e.g., cyclopentane),-   (2) a neopentyl group, or-   (3) a trimethylsilylmethyl group.

In another embodiment, R¹ is preferably

-   (1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   Q is a carbon atom, a silicon atom or a germanium atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (b) a hydroxy group,    -   (c) a C₆₋₁₄ aryl group (e.g., phenyl),    -   (d) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (e) a cyano group,    -   (f) a carbamoyl group optionally mono- or di-substituted by        C₃₋₁₀ cycloalkyl group(s) (e.g., cyclopropyl), or    -   (g) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or    -   R^(1a) and R^(1b) in combination form, together with the        adjacent Q, a C₃₋₁₀ cycloalkane ring (e.g., cyclopentane),-   (2) a neopentyl group, or-   (3) a trimethylsilylmethyl group.

In another embodiment, R¹ is preferably

-   (1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   Q is a carbon atom, a silicon atom or a germanium atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (b) a hydroxy group, or    -   (c) a cyano group,-   (2) a neopentyl group, or-   (3) a trimethylsilylmethyl group.

In another embodiment, R¹ is preferably

-   (1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   Q is a carbon atom, a silicon atom or a germanium atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (b) a hydroxy group, or    -   (c) a cyano group,-   (2) a neopentyl group, or-   (3) a trimethylsilylmethyl group.

R¹ is more preferably

-   (1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently a C₁₋₆ alkyl        group (e.g., methyl), or-   (2) a neopentyl group.

R¹ is further more preferably a group represented by the formula:-Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently a C₁₋₆ alkyl        group (e.g., methyl).

In another embodiment, R¹ is preferably

-   (1) a tert-butyl group,-   (2) a neopentyl group,-   (3) a trimethylsilyl group,-   (4) a 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl group,-   (5) a dimethylphenylsilyl group,-   (6) a trimethylsilylmethyl group,-   (7) a trimethylgermyl group,-   (8) a cyclopropyldimethylsilyl group,-   (9) a cyclopropyldimethylgermyl group,-   (10) an ethyldimethylsilyl group,-   (11) a 1-cyanocyclopentyl group,-   (12) a 1-(cyclopropylamino)-2-methyl-1-oxopropan-2-yl group,-   (13) a 2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl group, or-   (14) a 1-methoxy-2-methylpropan-2-yl group.

R¹ is more preferably

-   (1) a tert-butyl group,-   (2) a neopentyl group, or-   (3) a trimethylsilyl group.

R¹ is further more preferably

-   (1) a tert-butyl group, or-   (2) a trimethylsilyl group.

R² is

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is an optionally substituted alkyl group or an optionally        substituted alkoxy group, and    -   the benzene ring in the formula optionally has additional        substituent(s) besides R⁵,

-   (2) an optionally substituted bicyclic fused heterocyclic group, or

-   (3) a group represented by the formula: -L-Z¹    -   wherein    -   L is a bond or CH₂, and    -   Z¹ is an optionally substituted non-aromatic ring group.

Examples of the “optionally substituted alkyl group” represented by R⁵include a C₁₋₆ alkyl group optionally having 1 to 3 substituentsselected from Substituent Group A.

Examples of the “optionally substituted alkoxy group” represented by R⁵include a C₁₋₆ alkoxy group optionally having 1 to 3 substituentsselected from Substituent Group A.

Examples of the “bicyclic fused heterocyclic group” of the “optionallysubstituted bicyclic fused heterocyclic group” represented by R⁵ includebicyclic groups from among the above-mentioned 8- to 14-membered fusedpolycyclic aromatic heterocyclic group and 9- to 14-membered fusedpolycyclic non-aromatic heterocyclic group.

The “bicyclic fused heterocyclic group” is optionally substituted, forexample, by substituent(s) selected from Substituent Group A. The numberof the substituents is, for example, 1 to 3. When the number of thesubstituents is 2 or more, the respective substituents may be the sameor different.

Examples of the “optionally substituted non-aromatic ring group”represented by Z¹ include a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenylgroup and a non-aromatic heterocyclic group, each of which optionallyhas 1 to 3 substituents selected from Substituent Group A.

R² is preferably

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is    -   (A) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (a) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy)            optionally substituted by 1 to 3 substituents selected from            -   (i) a halogen atom (e.g., a fluorine atom), and            -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy), and        -   (b) a hydroxy group, or    -   (B) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy)        optionally substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g.,        methoxy), and    -   the benzene ring in the formula optionally has, besides R⁵,        additional 1 to 3 substituents selected from        -   (A) a C₁₋₆ alkyl group (e.g., methyl), and        -   (B) a C₁₋₆ alkoxy group (e.g., methoxy),

-   (2) a bicyclic fused heterocyclic group (e.g., dihydrobenzofuryl    (2,3-dihydrobenzofuryl), indazolyl (1H-indazolyl, 2H-indazolyl),    indolyl, indolinyl) optionally substituted by 1 to 3 C₁₋₆ alkyl    groups (e.g., methyl), or

-   (3) a group represented by the formula -L-Z¹:    -   wherein    -   L is a bond; and    -   Z¹ is    -   (A) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally        substituted by 1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom), and        -   (b) a hydroxy group, or    -   (B) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, piperidyl,        1,1-dioxidotetrahydrothiopyranyl) optionally substituted by C₁₋₆        alkyl group(s) (e.g., ethyl) optionally substituted by 1 to 3        halogen atoms (e.g., a fluorine atom).

R² is more preferably

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is    -   (A) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), or    -   (B) a C₁₋₆ alkoxy group (e.g., methoxy),

-   (2) a bicyclic fused heterocyclic group (e.g., dihydrobenzofuryl    (2,3-dihydrobenzofuryl), indazolyl (1H-indazolyl)) optionally    substituted by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl), or

-   (3) a group represented by the formula -L-Z¹:    -   wherein    -   L is a bond; and    -   Z¹ is    -   (A) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or    -   (B) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl).

R² is further more preferably

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is C₁₋₆ alkoxy group (e.g., methoxy),

-   (2) a bicyclic fused heterocyclic group (e.g., indazolyl    (1H-indazolyl)) optionally substituted by 1 to 3 C₁₋₆ alkyl groups    (e.g., methyl), or

-   (3) a group represented by the formula -L-Z¹:    -   wherein    -   L is a bond; and    -   Z¹ is a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom).

In another embodiment, R² is preferably

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is    -   (A) an alkoxy group (e.g., methoxy, ethoxy, propoxy) optionally        substituted by 1 to 3 alkoxy groups (e.g., methoxy),    -   (B) an alkyl group (e.g., methyl, ethyl, isopropyl) optionally        substituted by hydroxy group(s), or    -   (C) an alkoxyalkyl group (e.g., methoxymethyl, ethoxymethyl,        propoxymethyl, 1-methoxyethyl) optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) an alkoxy group (e.g., methoxy), and the benzene ring            in the formula optionally has, besides R⁵, additional 1 to 3            substituents selected from        -   (A) alkyl group (e.g., methyl), and        -   (B) an alkoxy group (e.g., methoxy),

-   (2) a tetrahydro-2H-pyran-4-yl group,

-   (3) a 4,4-difluorocyclohexyl group,

-   (4) a 1-methyl-1H-indazol-5-yl group,

-   (5) a 2,3-dihydro-1-benzofuran-5-yl group,

-   (6) a 1-(2,2,2-trifluoroethyl)piperidin-4-yl group,

-   (7) a 1,1-dioxidotetrahydro-2H-thiopyran-4-yl group,

-   (8) a 4,4-difluoro-1-hydroxycyclohexyl group,

-   (9) a 1-methylindol-5-yl group,

-   (10) a 1-methyl-2,3-dihydroindol-5-yl group, or

-   (11) a 2-methyl-2H-indazol-5-yl group.

R² is more preferably

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is an alkoxy group (e.g., methoxy) or an alkoxyalkyl group        (e.g., methoxymethyl),

-   (2) a tetrahydro-2H-pyran-4-yl group

-   (3) a 4,4-difluorocyclohexyl group

-   (4) a 1-methylindazol-5-yl group, or

-   (5) a 2,3-dihydro-1-benzofuran-5-yl group.

R¹ is further more preferably

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is an alkoxy group (e.g., methoxy)),

-   (2) a 4,4-difluorocyclohexyl group, or

-   (3) a 1-methylindazol-5-yl group.

Examples of the above-mentioned “alkyl group” include a C₁₋₆ alkylgroup. Examples of the above-mentioned “alkoxy group” include a C₁₋₆alkoxy group. Examples of the above-mentioned “alkoxyalkyl group”include a C₁₋₆ alkyl group substituted by 1 or 2 C₁₋₆ alkoxy groups.Specific examples thereof include methoxymethyl, ethoxymethyl,propoxymethyl, isopropoxymethyl, 1-methoxyethyl, 1-ethoxyethyl,1-propoxyethyl, 1-isopropoxyethyl, 2-methoxyethyl, 2-ethoxyethyl,2-propoxyethyl, 2-isopropoxyethyl and the like.

R³ is a hydrogen atom or a substituent, and

R⁴ is a substituent (provided that a group represented by the formula:

-   -   wherein    -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a        substituent, or a nitrogen atom,    -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a        substituent, or a nitrogen atom,    -   A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a        substituent, or a nitrogen atom, or    -   when A² is CR^(A2) wherein R^(A2) is a substituent, and A³ is        CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and R^(A3)        in combination optionally form, together with the carbon atoms        that they are bonded to, a hydrocarbon ring or a heterocycle,        and    -   R⁹ is a hydrogen atom or a hydroxy group, and when R⁹ is a        hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and        CR^(A), respectively,    -   is excluded), or        when R³ is a substituent, then R⁵ and R⁴ in combination        optionally form, together with the nitrogen atom adjacent to R³        and the carbon atom adjacent to R⁴, an optionally substituted        ring.

In another embodiment,

R³ is a hydrogen atom or a substituent, and

R⁴ is a substituent (provided that

-   -   (1) a group represented by the formula:

-   -   -   wherein        -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a            substituent, or a nitrogen atom, or        -   when A² is CR^(A2) wherein R^(A2) is a substituent, and A³            is CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and            R^(A3) in combination optionally form, together with the            carbon atoms that they are bonded to, a hydrocarbon ring or            a heterocycle,        -   R⁹ is a hydrogen atom or a hydroxy group, and when R⁹ is a            hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and            CR^(A), respectively, and        -   R¹⁰ is a hydroxy group or an optionally substituted C₁₋₆            alkoxy group, and

    -   (2) an optionally substituted C₁₋₆ alkoxy group are excluded),        or        when R³ is a substituent, then R⁵ and R⁴ in combination        optionally form, together with the nitrogen atom adjacent to R³        and the carbon atom adjacent to R⁴, an optionally substituted        ring (provided that

    -   (1) a cyclic group represented by the formula:

-   -   -   wherein X is CH or a nitrogen atom, which is optionally            further substituted, and

    -   (2) a cyclic group represented by the formula:

-   -   are excluded), and        the substituents that the ring optionally has optionally form a        spiro ring.

In yet another embodiment,

R³ is a hydrogen atom or a substituent, and

R⁴ is a substituent (provided that

-   -   (1) a group represented by the formula:

-   -   -   wherein        -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a            substituent, or a nitrogen atom,        -   A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a            substituent, or a nitrogen atom, or        -   when A² is CR^(A2) wherein R^(A2) is a substituent, and A³            is CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and            R^(A3) in combination optionally form, together with the            carbon atoms that they are bonded to, a hydrocarbon ring or            a heterocycle,        -   R⁹ is a hydrogen atom or a hydroxy group, and when R⁹ is a            hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and            CR^(A), respectively, and        -   R¹⁰ is a hydroxy group or an optionally substituted C₁₋₆            alkoxy group, and

    -   (2) an optionally substituted C₁₋₆ alkoxy group are excluded),        or        when R³ is a substituent, then R⁵ and R⁴ in combination        optionally form, together with the nitrogen atom adjacent to R³        and the carbon atom adjacent to R⁴, an optionally substituted        ring, and the substituents that the ring optionally has        optionally form a spiro ring.

Examples of the “substituent” represented by the above-mentioned R^(A1),R^(A2) or R^(A3) include Substituent Group AA selected from thefollowings, respectively, regardless of the above-mentioned description.

[Substituent Group AA]

-   (1) a halogen atom;-   (2) a nitro group;-   (3) a cyano group;-   (4) a carboxy group;-   (5) an optionally substituted C₁₋₁₂ alkyl group;-   (6) an optionally substituted C₂₋₁₂ alkenyl group;-   (7) an optionally substituted C₂₋₁₂ alkynyl group;-   (8) an optionally substituted C₃₋₁₂ cycloalkyl group;-   (9) an optionally substituted C₆₋₁₄ aryl group;-   (10) an optionally substituted C₇₋₁₆ aralkyl group;-   (11) an optionally substituted C₆₋₁₄ aryl-C₂₋₁₂ alkenyl group;-   (12) an optionally substituted heterocyclic group;-   (13) a hydroxy group;-   (14) an optionally substituted C₁₋₁₂ alkoxy group;-   (15) an optionally substituted C₃₋₁₂ cycloalkyloxy group;-   (16) an optionally substituted C₆₋₁₄ aryloxy group;-   (17) an optionally substituted C₇₋₁₆ aralkyloxy group;-   (18) an optionally substituted C₁₋₁₂ alkyl-carbonyloxy group;-   (19) an optionally substituted C₁₋₁₂ alkoxy-carbonyloxy group;-   (20) an optionally substituted mono-C₁₋₁₂ alkyl-carbamoyloxy group;-   (21) an optionally substituted di-C₁₋₁₂ alkyl-carbamoyloxy group;-   (22) an optionally substituted C₆₋₁₄ aryl-carbonyloxy group;-   (23) an optionally substituted mono- or di-C₆₋₁₄ aryl-carbamoyloxy    group;-   (24) an optionally substituted heterocyclyl-oxy group;-   (25) an optionally substituted C₁₋₁₂ alkylsulfonyloxy group;-   (26) a pentafluorosulfanyl group;-   (27) an optionally substituted C₁₋₁₂ alkylsulfanyl group;-   (28) an optionally substituted C₃₋₁₀ cycloalkylsulfanyl group;-   (29) an optionally substituted C₆₋₁₄ arylsulfanyl group;-   (30) an optionally substituted C₇₋₁₆ aralkylsulfanyl group;-   (31) an optionally substituted heterocyclyl-sulfanyl group;-   (32) a formyl group;-   (33) an optionally substituted C₁₋₁₂ alkyl-carbonyl group;-   (34) an optionally substituted C₃₋₁₂ cycloalkyl-carbonyl group;-   (35) an optionally substituted C₅₋₁₄ aryl-carbonyl group;-   (36) an optionally substituted C₇₋₁₆ aralkyl-carbonyl group;-   (37) an optionally substituted heterocyclyl-carbonyl group;-   (38) an optionally substituted C₁₋₁₂ alkylsulfonyl group;-   (39) an optionally substituted C₃₋₁₂ cycloalkylsulfonyl group;-   (40) an optionally substituted C₆₋₁₄ arylsulfonyl group;-   (41) an optionally substituted C₇₋₁₆ aralkylsulfonyl group;-   (42) an optionally substituted heterocyclyl-sulfonyl group;-   (43) an optionally substituted C₁₋₁₂ alkylsulfinyl group;-   (44) an optionally substituted C₃₋₁₂ cycloalkylsulfinyl group;-   (45) an optionally substituted C₆₋₁₄ arylsulfinyl group;-   (46) an optionally substituted C₇₋₁₅ aralkylsulfinyl group;-   (47) an optionally substituted heterocyclyl-sulfinyl group;-   (48) a sulfo group;-   (49) an optionally substituted sulfamoyl group;-   (50) an optionally substituted sulfinamoyl group;-   (51) an optionally substituted sulfenamoyl group;-   (52) an optionally substituted thiocarbamoyl group;-   (53) an optionally substituted carbamoyl group    [e.g.,    a carbamoyl group,    an optionally substituted mono- or di-C₁₋₁₂ alkyl-carbamoyl group,    an optionally substituted mono- or di-C₁₋₁₂ cycloalkyl-carbamoyl    group,    an optionally substituted mono- or di-C₆₋₁₄ aryl-carbamoyl group,    an optionally substituted mono- or di-heterocyclyl-carbamoyl group    and the like];-   (54) an optionally substituted amino group    [e.g.,    an amino group,    an optionally substituted mono- or di-C₁₋₁₂ alkyl-amino group,    an optionally substituted mono- or di-C₃₋₁₂ cycloalkyl-amino group,    an optionally substituted mono- or di-C₆₋₁₄ aryl-amino group,    an optionally substituted mono- or di-C₇₋₁₆ aralkyl-amino group,    an optionally substituted mono- or di-heterocyclyl-amino group,    an optionally substituted mono- or di-C₆₋₁₄ aryl-carbonylamino    group,    a formylamino group,    an optionally substituted mono- or di-(C₁₋₁₂ alkyl-carbonyl)amino    group,    an optionally substituted mono- or di-(C₃₋₁₂    cycloalkyl-carbonyl)amino group,    an optionally substituted mono- or di-(heterocyclyl-carbonyl)amino    group,    an optionally substituted mono- or di-(C₁₋₁₂ alkoxy-carbonyl)amino    group,    an optionally substituted mono- or di-(C₃₋₁₀    cycloalkoxy-carbonyl)amino group,    an optionally substituted mono- or    di-(heterocyclyl-oxycarbonyl)amino group,    an optionally substituted mono- or di-(C₁₋₁₂ alkylsulfonyl)amino    group,    an optionally substituted mono- or di-(C₃₋₁₂    cycloalkylsulfonyl)amino group,    an optionally substituted mono- or di-(C₆₋₁₄ arylsulfonyl)amino    group,    an optionally substituted heterocyclyl-sulfonylamino group and the    like];-   (55) an optionally substituted C₁₋₁₂ alkoxy-carbonyl group;-   (56) an optionally substituted C₅₋₁₄ aryloxy-carbonyl group;-   (57) an optionally substituted C₇₋₁₆ aralkyloxy-carbonyl group;-   (58) an optionally substituted heterocyclyloxy-carbonyl group;-   (59) an optionally substituted tri-C₁₋₁₂ alkylsilyl group;-   (60) an optionally substituted (C₃₋₁₂ cycloalkyl)di(C₁₋₁₂    alkyl)silyl group;-   (61) an optionally substituted (C₆₋₁₄ aryl)di(C₁₋₁₂ alkyl)silyl    group;-   (62) an optionally substituted (C₁₋₁₂ alkyl)di(C₆₋₁₄ aryl)silyl    group;-   (63) an optionally substituted tri-C₁₋₁₂ alkylgermyl group;-   (64) an optionally substituted (C₃₋₁₀ cycloalkyl)di(C₁₋₁₂    alkyl)germyl group;-   (65) an optionally substituted (C₆₋₁₄ aryl)di(C₁₋₁₂ alkyl)germyl    group;-   (66) an optionally substituted (C₁₋₁₂ alkyl)di(C₆₋₁₄ aryl)germyl    group;-   (67) an oxo group    and the like.

Examples of the substituent of

-   -   the “optionally substituted C₁₋₁₂ alkyl group”,    -   “optionally substituted C₂₋₁₂ alkenyl group”,    -   “optionally substituted C₂₋₁₂ alkynyl group”,    -   “optionally substituted C₁₋₁₂ alkoxy group”,    -   “optionally substituted C₁₋₁₂ alkyl-carbonyloxy group”,    -   “optionally substituted C₁₋₁₂ alkoxy-carbonyloxy group”,    -   “optionally substituted mono- or di-C₁₋₁₂ alkyl-carbamoyl        group”,    -   “optionally substituted mono-C₁₋₁₂ alkyl-carbamoyloxy group”,    -   “optionally substituted di-C₁₋₁₂ alkyl-carbamoyloxy group”,    -   “optionally substituted C₁₋₁₂ alkylsulfonyloxy group”,    -   “optionally substituted C₁₋₁₂ alkylsulfanyl group”,    -   “optionally substituted C₁₋₁₂ alkyl-carbonyl group”,    -   “optionally substituted C₁₋₁₂ alkylsulfonyl group”,    -   “optionally substituted C₁₋₁₂ alkylsulfinyl group”,    -   “optionally substituted sulfamoyl group”,    -   “optionally substituted sulfinamoyl group”,    -   “optionally substituted sulfenamoyl group”,    -   “optionally substituted thiocarbamoyl group”,    -   “optionally substituted mono- or di-C₁₋₁₂ alkyl-carbamoyl        group”,    -   “optionally substituted mono- or di-C₁₋₁₂ alkyl-amino group”,    -   “optionally substituted mono- or di-(C₁₋₁₂ alkyl-carbonyl)amino        group”,    -   “optionally substituted mono- or di-(C₁₋₁₂ alkoxy-carbonyl)amino        group”,    -   “optionally substituted mono- or di-(C₁₋₁₂ alkylsulfonyl)amino        group”,    -   “optionally substituted C₁₋₁₂ alkoxy-carbonyl group”,    -   “optionally substituted tri-C₁₋₁₂ alkylsilyl group”, and    -   “optionally substituted tri-C₁₋₁₂ alkylgermyl group” in        Substituent Group AA include substituents selected from the        following Substituent Group BB. The number of the substituents        is 1 to substitutable maximum number, preferably 1 to 7, more        preferably 1 to 3.

Examples of the substituent of

-   -   the “optionally substituted C₃₋₁₂ cycloalkyl group”,    -   “optionally substituted C₆₋₁₄ aryl group”,    -   “optionally substituted C₇₋₁₆ aralkyl group”,    -   “optionally substituted C₆₋₁₄ aryl-C₂₋₁₂ alkenyl group”,    -   “optionally substituted heterocyclic group”,    -   “optionally substituted C₃₋₁₂ cycloalkyloxy group”,    -   “optionally substituted C₆₋₁₄ aryloxy group”,    -   “optionally substituted C₇₋₁₆ aralkyloxy group”,    -   “optionally substituted heterocyclyl-oxy group”,    -   “optionally substituted C₆₋₁₄ aryl-carbonyloxy group”,    -   “optionally substituted mono- or di-C₃₋₁₂ cycloalkyl-carbamoyl        group”,    -   “optionally substituted mono- or di-C₆₋₁₄ aryl-carbamoyl group”,    -   “optionally substituted mono- or di-heterocyclyl-carbamoyl        group”,    -   “optionally substituted mono- or di-C₆₋₁₄ aryl-carbamoyloxy        group”,    -   “optionally substituted C₃₋₁₂ cycloalkylsulfanyl group”,    -   “optionally substituted C₆₋₁₄ arylsulfanyl group”,    -   “optionally substituted C₇₋₁₆ aralkylsulfanyl group”,    -   “optionally substituted heterocyclyl-sulfanyl group”,    -   “optionally substituted C₃₋₁₂ cycloalkyl-carbonyl group”,    -   “optionally substituted C₆₋₁₄ aryl-carbonyl group”,    -   “optionally substituted C₇₋₁₆ aralkyl-carbonyl group”,    -   “optionally substituted heterocyclyl-carbonyl group”,    -   “optionally substituted C₃₋₁₂ cycloalkylsulfonyl group”,    -   “optionally substituted C₆₋₁₄ arylsulfonyl group”,    -   “optionally substituted heterocyclyl-sulfonyl group”,    -   “optionally substituted C₃₋₁₀ cycloalkylsulfinyl group”,    -   “optionally substituted C₆₋₁₄ arylsulfinyl group”,    -   “optionally substituted C₇₋₁₆ aralkylsulfinyl group”,    -   “optionally substituted heterocyclyl-sulfinyl group”,    -   “optionally substituted mono- or di-C₃₋₁₀ cycloalkyl-amino        group”,    -   “optionally substituted mono- or di-C₆₋₁₄ aryl-amino group”,    -   “optionally substituted mono- or di-C₇₋₁₆ aralkyl-amino group”,    -   “optionally substituted mono- or di-heterocyclyl-amino group”,    -   “optionally substituted mono- or di-C₆₋₁₄ aryl-carbonylamino        group”,    -   “optionally substituted mono- or di-(C₃₋₁₂        cycloalkyl-carbonyl)amino group”,    -   “optionally substituted mono- or di-(heterocyclyl-carbonyl)amino        group”,    -   “optionally substituted mono- or di-(C₃₋₁₂        cycloalkoxy-carbonyl)amino group”,    -   “optionally substituted mono- or        di-(heterocyclyl-oxycarbonyl)amino group”,    -   “optionally substituted mono- or di-(C₃₋₁₂        cycloalkylsulfonyl)amino group”,    -   “optionally substituted mono- or di-(C₆₋₁₄ arylsulfonyl)amino        group”,    -   “optionally substituted heterocyclyl-sulfonylamino group”,    -   “optionally substituted C₆₋₁₄ aryloxy-carbonyl group”,    -   “optionally substituted C₇₋₁₆ aralkyloxy-carbonyl group”,    -   “optionally substituted heterocyclyloxy-carbonyl group”,    -   “optionally substituted (C₃₋₁₂ cycloalkyl)di(C₁₋₁₂ alkyl)silyl        group”,    -   “optionally substituted (C₆₋₁₄ aryl)di(C₁₋₁₂ alkyl)silyl group”,    -   “optionally substituted (C₁₋₁₂ alkyl)di(C₆₋₁₄ aryl) silyl        group”,    -   “optionally substituted (C₃₋₁₂ cycloalkyl)di(C₁₋₁₂ alkyl)germyl        group”,    -   “optionally substituted (C₆₋₁₄ aryl)di(C₁₋₁₂ alkyl)germyl        group”, and    -   “optionally substituted (C₁₋₁₂ alkyl)di(C₆₋₁₄ aryl)germyl group”        in Substituent Group AA include substituents selected from the        following Substituent Group BB and Substituent Group BB′. The        number of the substituents is 1 to substitutable maximum number,        more preferably 1 to 3, further more preferably 1.

In the present specification, Substituent Group BB consists of

-   -   (a) a halogen atom;    -   (b) a hydroxy group;    -   (c) a nitro group;    -   (d) a cyano group;    -   (e) an optionally substituted C₆₋₁₄ aryl group (the C₆₋₁₄ aryl        group is optionally substituted by 1 to 5 (preferably 1 to 3,        more preferably 1) substituents selected from a halogen atom, a        hydroxy group, a cyano group, an amino group, a C₁₋₁₂ alkyl        group optionally substituted by 1 to 3 halogen atoms, a mono- or        di-C₁₋₁₂ alkyl-amino group, a mono- or di-C₆₋₁₄ aryl-amino        group, a mono- or di-C₇₋₁₆ aralkyl-amino group, a C₃₋₁₂        cycloalkyl group, a C₁₋₁₂ alkoxy group, a formyl group, a C₁₋₁₂        alkyl-carbonyl group, a C₃₋₁₂ cycloalkyl-carbonyl group, a C₆₋₁₄        aryl-carbonyl group, a C₇₋₁₆ aralkyl-carbonyl group, a C₁₋₁₂        alkoxy-carbonyl group, a C₆₋₁₄ aryloxy-carbonyl group, a C₇₋₁₆        aralkyloxy-carbonyl group, a C₁₋₁₂ alkylsulfanyl group, a C₁₋₁₂        alkylsulfinyl group, a C₁₋₁₂ alkylsulfonyl group, a carbamoyl        group, a thiocarbamoyl group, a mono- or di-C₁₋₁₂        alkyl-carbamoyl group, a mono- or di-C₆₋₁₄ aryl-carbamoyl group        and the like);    -   (f) an optionally substituted C₆₋₁₄ aryloxy group (the C₆₋₄        aryloxy group is optionally substituted by 1 to 5 (preferably 1        to 3, more preferably 1) substituents selected from a halogen        atom, a hydroxy group, a cyano group, an amino group, a C₁₋₁₂        alkyl group optionally substituted by 1 to 3 halogen atoms, a        mono- or di-C₁₋₁₂ alkyl-amino group, a mono- or di-C₆₋₁₄        aryl-amino group, a mono- or di-C₇₋₁₆ aralkyl-amino group, a        C₃₋₁₂ cycloalkyl group, a C₁₋₁₂ alkoxy group, a formyl group, a        C₁₋₁₂ alkyl-carbonyl group, a C₃₋₁₂ cycloalkyl-carbonyl group, a        C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆ aralkyl-carbonyl group, a        C₁₋₁₂ alkoxy-carbonyl group, a C₆₋₁₄ aryloxy-carbonyl group, a        C₇₋₁₆ aralkyloxy-carbonyl group, a C₁₋₁₂ alkylsulfanyl group, a        C₁₋₁₂ alkylsulfinyl group, a C₁₋₁₂ alkylsulfonyl group, a        carbamoyl group, a thiocarbamoyl group, a mono- or di-C₁₋₁₂        alkyl-carbamoyl group, a mono- or di-C₆₋₁₄ aryl-carbamoyl group        and the like);    -   (g) an optionally substituted C₇₋₁₆ aralkyloxy group (the C₇₋₁₆        aralkyloxy group is optionally substituted by 1 to 5 (preferably        1 to 3, more preferably 1) substituents selected from a halogen        atom, a hydroxy group, a cyano group, an amino group, a C₁₋₁₂        alkyl group optionally substituted by 1 to 3 halogen atoms, a        mono- or di-C₁₋₁₂ alkyl-amino group, a mono- or di-C₆₋₁₄        aryl-amino group, a mono- or di-C₇₋₁₆ aralkyl-amino group, a        C₃₋₁₂ cycloalkyl group, a C₁₋₁₂ alkoxy group, a formyl group, a        C₁₋₁₂ alkyl-carbonyl group, a C₃₋₁₂ cycloalkyl-carbonyl group, a        C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆ aralkyl-carbonyl group, a        C₁₋₁₂ alkoxy-carbonyl group, a C₆₋₁₄ aryloxy-carbonyl group, a        C₇₋₁₆ aralkyloxy-carbonyl group, a C₁₋₁₂ alkylsulfanyl group, a        C₁₋₁₂ alkylsulfinyl group, a C₁₋₁₂ alkylsulfonyl group, a        carbamoyl group, a thiocarbamoyl group, a mono- or di-C₁₋₁₂        alkyl-carbamoyl group, a mono- or di-C₆₋₁₄ aryl-carbamoyl group        and the like);    -   (h) an optionally substituted 3- to 14-membered heterocyclic        group containing 1 to 5 heteroatoms selected from a nitrogen        atom, a sulfur atom and an oxygen atom (the heterocyclic group        is optionally substituted by 1 to 5 (preferably 1 to 3, more        preferably 1) substituents selected from a halogen atom, a        hydroxy group, a cyano group, an amino group, a C₁₋₁₂ alkyl        group optionally substituted by 1 to 3 halogen atoms, a mono- or        di-C₁₋₁₂ alkyl-amino group, a mono- or di-C₆₋₁₄ aryl-amino        group, a mono- or di-C₇₋₁₆ aralkyl-amino group, a C₃₋₁₂        cycloalkyl group, a C₁₋₁₂ alkoxy group, a formyl group, a C₁₋₁₂        alkyl-carbonyl group, a C₃₋₁₀ cycloalkyl-carbonyl group, a C₆₋₁₄        aryl-carbonyl group, a C₇₋₁₆ aralkyl-carbonyl group, a C₁₋₁₂        alkoxy-carbonyl group, a C₆₋₁₄ aryloxy-carbonyl group, a C₇₋₁₆        aralkyloxy-carbonyl group, a C₁₋₁₂ alkylsulfanyl group, a C₁₋₁₂        alkylsulfinyl group, a C₁₋₁₂ alkylsulfonyl group, a carbamoyl        group, a thiocarbamoyl group, a mono- or di-C₁₋₁₂        alkyl-carbamoyl group, a mono- or di-C₆₋₁₄ aryl-carbamoyl group        and the like);    -   (i) an optionally substituted amino group {for example, an amino        group optionally mono- or di-substituted by substituent(s)        selected from the group consisting of a C₁₋₁₂ alkyl group, a        C₂₋₁₂ alkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group,        a heterocyclic group and a heterocyclyl-C₁₋₁₂ alkyl group [the        C₁₋₁₂ alkyl group, C₂₋₁₂ alkenyl group, C₆₋₁₄ aryl group, C₇₋₁₆        aralkyl group, heterocyclic group and heterocyclyl-C₁₋₁₂ alkyl        group are each optionally substituted by 1 to 5 (preferably 1 to        3, more preferably 1) substituents selected from a halogen atom,        a hydroxy group, a cyano group, an amino group, a C₁₋₁₂ alkyl        group optionally substituted by 1 to 3 halogen atoms (provided        that the “C₁₋₆ alkyl group optionally substituted by 1 to 3        halogen atoms” is not a substituent for the C₁₋₁₂ alkyl group        and C₂₋₁₂ alkenyl group), a mono- or di-C₁₋₁₂ alkyl-amino group,        a mono- or di-C₆₋₁₄ aryl-amino group, a mono- or di-C₇₋₁₆        aralkyl-amino group, a C₃₋₁₂ cycloalkyl group, a C₁₋₁₂ alkoxy        group, a formyl group, a C₁₋₁₂ alkyl-carbonyl group, a C₃₋₁₂        cycloalkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆        aralkyl-carbonyl group, a C₁₋₁₂ alkoxy-carbonyl group, a C₃₋₁₂        cycloalkyloxy-carbonyl group, a C₆₋₁₄ aryloxy-carbonyl group, a        C₇₋₁₆ aralkyloxy-carbonyl group, a C₁₋₁₂ alkylsulfanyl group, a        C₃₋₁₂ cycloalkylsulfanyl group, a C₁₋₁₂ alkylsulfinyl group, a        C₃₋₁₂ cycloalkylsulfinyl group, a C₁₋₁₂ alkylsulfonyl group, a        C₃₋₁₂ cycloalkylsulfonyl group, a carbamoyl group, a        thiocarbamoyl group, a mono- or di-C₁₋₁₂ alkyl-carbamoyl group,        a mono- or di-C₆₋₁₄ aryl-carbamoyl group and the like]};    -   (j) a C₃₋₁₂ cycloalkyl group;    -   (k) an optionally substituted C₁₋₁₂ alkoxy group (the C₁₋₁₂        alkoxy group is optionally substituted by 1 to 5 (preferably 1        to 3, more preferably 1) substituents selected from a halogen        atom, a hydroxy group, an amino group, a mono- or di-C₁₋₁₂        alkyl-amino group, a mono- or di-C₆₋₁₄ aryl-amino group, a C₃₋₁₀        cycloalkyl group, a C₁₋₁₂ alkoxy group, a formyl group, a C₁₋₁₂        alkyl-carbonyl group, a C₃₋₁₀ cycloalkyl-carbonyl group, a C₆₋₁₄        aryl-carbonyl group, a C₇₋₁₆ aralkyl-carbonyl group, a C₁₋₁₂        alkoxy-carbonyl group, a C₆₋₁₄ aryloxy-carbonyl group, a C₇₋₁₆        aralkyloxy-carbonyl group, a C₁₋₁₂ alkylsulfanyl group, a C₁₋₁₂        alkylsulfinyl group, a C₁₋₁₂ alkylsulfonyl group, a carbamoyl        group, a thiocarbamoyl group, a mono- or di-C₁₋₁₂        alkyl-carbamoyl group, a mono- or di-C₆₋₁₄ aryl-carbamoyl group,        a tri-C₁₋₁₂ alkylsilyl group (e.g., trimethylsilyl) and the        like);    -   (l) a formyl group;    -   (m) a C₁₋₁₂ alkyl-carbonyl group (e.g., acetyl);    -   (n) a C₃₋₁₂ cycloalkyl-carbonyl group;    -   (o) a C₆₋₁₄ aryl-carbonyl group;    -   (p) a C₇₋₁₆ aralkyl-carbonyl group;    -   (q) a C₁₋₁₂ alkoxy-carbonyl group;    -   (r) a C₆₋₁₄ aryloxy-carbonyl group;    -   (s) a C₇₋₁₆ aralkyloxy-carbonyl group;    -   (t) a C₁₋₁₂ alkylsulfanyl group;    -   (u) a C₁₋₁₂ alkylsulfinyl group;    -   (v) a C₁₋₁₂ alkylsulfonyl group;    -   (w) a carbamoyl group;    -   (x) a thiocarbamoyl group;    -   (y) a mono- or di-C₁₋₁₂ alkyl-carbamoyl group (e.g.,        methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,        diethylcarbamoyl, ethylmethylcarbamoyl etc.);    -   (z) a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,        phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.);    -   (aa) a mono- or di-(5- to 7-membered heterocycle containing 1 to        4 heteroatoms selected from a nitrogen atom, a sulfur atom and        an oxygen atom)-carbamoyl group (e.g., 2-pyridylcarbamoyl,        3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl,        3-thienylcarbamoyl etc.);    -   (ab) a tri-C₁₋₁₂ alkylsilyl group (e.g., trimethylsilyl);    -   (ac) a (C₃₋₁₀ cycloalkyl)di(C₁₋₁₂ alkyl)silyl group;    -   (ad) a (C₆₋₁₄ aryl)di(C₁₋₁₂ alkyl) silyl group;    -   (ae) a (C₁₋₁₂ alkyl)di(C₆₋₁₄ aryl) silyl group;    -   (af) a tri-C₁₋₁₂ alkylgermyl group;    -   (ag) a (C₃₋₁₂ cycloalkyl)di(C₁₋₁₂ alkyl)germyl group;    -   (ah) a (C₆₋₁₄ aryl)di(C₁₋₁₂ alkyl) germyl group; and    -   (ai) a (C₁₋₁₂ alkyl)di(C₆₋₁₄ aryl) germyl group.

In the present specification, Substituent Group BB′ consists of

-   -   (a) an optionally substituted C₁₋₁₂ alkyl group (the C₁₋₁₂ alkyl        group is optionally substituted by 1 to 5 (preferably 1 to 3,        more preferably 1) substituents selected from a halogen atom, a        hydroxy group, a cyano group, an amino group, a mono- or        di-C₁₋₁₂ alkyl-amino group, a mono- or di-C₆₋₁₄ aryl-amino        group, a mono- or di-C₇₋₁₆ aralkyl-amino group, a C₃₋₁₂        cycloalkyl group, a C₁₋₁₂ alkoxy group, a formyl group, a C₁₋₁₂        alkyl-carbonyl group, a C₃₋₁₂ cycloalkyl-carbonyl group, a C₆₋₁₄        aryl-carbonyl group, a C₇₋₁₆ aralkyl-carbonyl group, a C₁₋₁₂        alkoxy-carbonyl group, a C₆₋₁₄ aryloxy-carbonyl group, a C₇₋₁₆        aralkyloxy-carbonyl group, a C₁₋₁₂ alkylsulfanyl group, a C₁₋₁₂        alkylsulfinyl group, a C₁₋₁₂ alkylsulfonyl group, a carbamoyl        group, a thiocarbamoyl group, a mono- or di-C₁₋₁₂        alkyl-carbamoyl group, a mono- or di-C₆₋₁₄ aryl-carbamoyl group        and the like);    -   (b) an optionally substituted C₂₋₁₂ alkenyl group (the C₂₋₁₂        alkenyl group is optionally substituted by 1 to 5 (preferably 1        to 3, more preferably 1) substituents selected from a halogen        atom, a hydroxy group, a cyano group, an amino group, a mono- or        di-C₁₋₁₂ alkyl-amino group, a mono- or di-C₆₋₁₄ aryl-amino        group, a mono- or di-C₇₋₁₆ aralkyl-amino group, a C₃₋₁₂        cycloalkyl group, a C₁₋₁₂ alkoxy group, a formyl group, a C₁₋₁₂        alkyl-carbonyl group, a C₃₋₁₂ cycloalkyl-carbonyl group, a C₆₋₁₄        aryl-carbonyl group, a C₇₋₁₆ aralkyl-carbonyl group, a C₁₋₁₂        alkoxy-carbonyl group, a C₆₋₁₄ aryloxy-carbonyl group, a C₇₋₁₆        aralkyloxy-carbonyl group, a C₁₋₁₂ alkylsulfanyl group, a C₁₋₁₂        alkylsulfinyl group, a C₁₋₁₂ alkylsulfonyl group, a carbamoyl        group, a thiocarbamoyl group, a mono- or di-C₁₋₁₂        alkyl-carbamoyl group, a mono- or di-C₆₋₁₄ aryl-carbamoyl group        and the like); and    -   (c) an optionally substituted C₂₋₁₂ alkynyl group (the C₂₋₁₂        alkynyl group is optionally substituted by 1 to 5 (preferably 1        to 3, more preferably 1) substituents selected from a halogen        atom, a hydroxy group, a cyano group, an amino group, a mono- or        di-C₁₋₁₂ alkyl-amino group, a mono- or di-C_(C-14) aryl-amino        group, a mono- or di-C₇₋₁₆ aralkyl-amino group, a C₃₋₁₂        cycloalkyl group, a C₁₋₁₂ alkoxy group, a formyl group, a C₁₋₁₂        alkyl-carbonyl group, a C₃₋₁₂ cycloalkyl-carbonyl group, a C₆₋₁₄        aryl-carbonyl group, a C₇₋₁₆ aralkyl-carbonyl group, a C₁₋₁₂        alkoxy-carbonyl group, a C₆₋₁₄ aryloxy-carbonyl group, a C₇₋₁₆        aralkyloxy-carbonyl group, a C₁₋₁₂ alkylsulfanyl group, a C₁₋₁₂        alkylsulfinyl group, a C₁₋₁₂ alkylsulfonyl group, a carbamoyl        group, a thiocarbamoyl group, a mono- or di-C₁₋₁₂        alkyl-carbamoyl group, a mono- or di-C₆₋₁₄ aryl-carbamoyl group        and the like).

The above-mentioned “Substituent Group AA”, “Substituent Group BB” and“Substituent Group BB′” each corresponds to the “Substituent Group A”,“Substituent Group B” and “Substituent Group B′” described in WO2013/100027, and the term of each substituent is as defined in WO2013/100027.

Examples of the “hydrocarbon ring” formed by R^(A2) and R^(A3) incombination together with the carbon atoms that they are bonded toinclude rings corresponding to the above-mentioned “C₃₋₁₀ cycloalkylgroup”, “C₃₋₁₀ cycloalkenyl group” and “C₆₋₁₄ aryl group”.

Examples of the “heterocycle” formed by R^(A2) and R^(A3) in combinationtogether with the carbon atoms that they are bonded to include a ringcorresponding to the above-mentioned “heterocyclic group”.

Examples of the “C₁₋₆alkoxy group” of the “optionally substitutedC₁₋₆alkoxy group” represented by R¹⁰ and the “(2) an optionallysubstituted C₁₋₆ alkoxy group” excluded from R⁴ is optionallysubstituted, for example, by substituent(s) selected from theabove-mentioned Substituent Group A.

The number of the substituents for the “C₁₋₆ alkoxy group” is, forexample, 1 to 3. When the number of the substituents is 2 or more, therespective substituents may be the same or different.

The “heterocyclic group” of the “optionally substituted heterocyclicgroup” exemplified as the “substituent” represented by R⁴ encompasses anaromatic heterocyclic group, a non-aromatic heterocyclic group and a 7-to 10-membered bridged heterocyclic group, as well as a 5- to14-membered spiro heterocyclic group such as 2-oxa-6-azaspiro[3.5]nonyl,2-oxa-6-azaspiro[3.4]octyl and the like.

The “ring” of the “optionally substituted ring” form by R³ and R⁴ incombination together with the nitrogen atom adjacent to R³ and thecarbon atom adjacent to R⁴ means a non-aromatic heterocycle contains atleast one nitrogen atom wherein the carbon atom adjacent to the nitrogenatom is substituted by an oxo group. Examples thereof includepyrrolidin-2-one, piperidin-2-one, morpholin-3-one and the like.

The ring is optionally fused with a hydrocarbon ring (e.g., a C₃₋₁₀cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexaneand the like, a benzene ring) or a heterocycle (e.g., an aromaticheterocycle such as a pyridine ring and the like, a non-aromaticheterocycle such as pyrrolidine, piperidine and the like). Examplesthereof include isoindolin-1-one, isoquinoline-1(2H)one,3,4-dihydroisoquinoline-1(2H)one and the like.

The ring optionally forms a spiro ring with a hydrocarbon ring (e.g., aC₃₋₁₀ cycloalkane such as cyclopropane, cyclobutane, cyclopentane,cyclohexane and the like, a benzene ring) or a heterocycle (e.g., anon-aromatic heterocycle such as pyrrolidine, piperidine and the like).Examples thereof include 2,7-diazaspiro[4.4]nonane-1,8-dione and thelike.

The “ring” of the “optionally substituted ring” form by R³ and R⁴ incombination together with the nitrogen atom adjacent to R³ and thecarbon atom adjacent to R⁴ is optionally substituted, for example, bysubstituent(s) selected from the above-mentioned Substituent Group A

The number of the substituents of the “optionally substituted ring” is,for example, 1 to 3. When the number of the substituents is 2 or more,the respective substituents may be the same or different.

The “substituent” represented by R³ is preferably an optionallysubstituted hydrocarbon group.

The “substituent” represented by R⁴ is preferably an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup, an acyl group, an optionally substituted amino group, or anoptionally substituted hydroxy group.

Examples of the “optionally substituted hydrocarbon group” exemplifiedas the “substituent” represented by R⁴ include a hydrocarbon groupoptionally having substituent(s) selected from the following SubstituentGroup B, regardless of the above-mentioned description.

[Substituent Group B]

(A) Substituent Group A wherein

“(9) a 5- to 14-membered aromatic heterocyclyloxy group” is replaced by“(9) a 5- to 14-membered aromatic heterocyclyloxy group optionallysubstituted by C₁₋₆ alkyl group(s)”,

“(21) a 5- to 14-membered aromatic heterocyclic group” is replaced by“(21) a 5- to 14-membered aromatic heterocyclic group optionallysubstituted by substituent(s) selected from (a) a C₁₋₆ alkyl groupoptionally substituted by substituent(s) selected from a halogen atomand a C₆₋₁₄ aryl group, (b) a hydroxy group and (c) a C₁₋₆alkoxy groupoptionally substituted by C₆₋₁₄ aryl group(s)”, and“(22) a 3- to 14-membered non-aromatic heterocyclic group” is replacedby “(22) a 3- to 14-membered non-aromatic heterocyclic group optionallysubstituted by substituent(s) selected from (a) an oxo group, (b) aC₁₋₁₂ alkyl group, (c) a hydroxy group and (d) a cyano group”, and(B) an imino group optionally substituted by a hydroxy group.

The number of the substituents of the above-mentioned “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is 2 or more, the respectivesubstituents may be the same or different.

Examples of the “optionally substituted heterocyclic group” exemplifiedas the “substituent” represented by R⁴ include a heterocyclic groupoptionally having substituent(s) selected from the following SubstituentGroup C, regardless of the above-mentioned description.

[Substituent Group C]

(A) Substituent Group A wherein

“(6) an optionally halogenated C₁₋₆ alkoxy group” is replaced by

“(6) a C₁₋₆ alkoxy group optionally substituted by substituent(s)selected from (a) a halogen atom and (b) a C₆₋₁₄ aryl group”, and

“(57) an optionally halogenated C₁₋₆ alkyl group” is replaced by

“(57) a C₁₋₆ alkyl group optionally substituted by substituent(s)selected from (a) a halogen atom and (b) a hydroxy group”, and

(B) a C₁₋₆ alkylidene group optionally substituted by 5- or 6-memberedmonocyclic aromatic heterocyclic group(s) optionally substituted bysubstituent(s) selected from (a) a C₁₋₆ alkyl group, and (b) ahalogenated boryl group.

The number of the substituents of the above-mentioned “optionallysubstituted heterocyclic group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is 2 or more, the respectivesubstituents may be the same or different.

Examples of the “C₁₋₆ alkylidene group” in the “substituent” representedby R⁴ include methylidene (═CH₂), ethylidene (═CH—CH₃), propylidene(═CH—CH₂—CH₃), buthylidene (═CH—CH₂—CH₂—CH₃) and the like.

R³ is preferably

-   (1) a hydrogen atom, or-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted    by 1 to 3 cyano groups.

R³ is more preferably

-   (1) a hydrogen atom, or-   (2) a C₁₋₆ alkyl group (e.g., methyl).

In another embodiment, R³ is preferably a hydrogen atom, a methyl group,an ethyl group or a 2-cyanoethyl group.

R³ is more preferably a hydrogen atom or a methyl group.

R⁴ is preferably

-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,    butyl, isobutyl, tert-butyl) optionally substituted by 1 to 7    substituents selected from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyrimidinyl (1,6-dihydropyrimidinyl),        dihydropyridyl (1,2-dihydropyridyl, 1,4-dihydropyridyl),        tetrahydropyrimidinyl (1,2,3,4-tetrahydropyrimidinyl),        dihydropyridazinyl (1,4-dihydropyridazinyl,        2,3-dihydropyridazinyl), imidazolidinyl, tetrahydropyranyl,        morpholinyl, piperidyl, dihydrooxadiazolyl        (4,5-dihydro-1,2,4-oxadiazolyl), pyrrolidinyl, tetrahydrofuryl,        piperazinyl, thiazolidinyl, oxazolidinyl, azetidinyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) an oxo group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),        -   (iii) a hydroxy group, and        -   (iv) a cyano group,    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl), isoxazolyl, pyrazolyl,        pyridyl, imidazolyl (1H-imidazolyl), thienyl, tetrazolyl        (1H-tetrazolyl)) optionally substituted by 1 to 3 substituents        selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally            substituted by 1 to 3 substituents selected from a halogen            atom (e.g., a fluorine atom) and a C₆₋₁₄ aryl group (e.g.,            phenyl),        -   (ii) a hydroxy group, and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),    -   (c) a 8- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) aromatic heterocyclic group (e.g., indazolyl        (1H-indazolyl), benzisoxazolyl (benzo[d]isoxazolyl),        benzimidazolyl (1H-benzimidazolyl)),    -   (d) a 9- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) non-aromatic heterocyclic group (e.g.,        dihydrobenzoxazolyl(2,3-dihydrobenzoxazolyl)) optionally        substituted by 1 to 3 oxo groups,    -   (e) a halogen atom (e.g., a fluorine atom),    -   (f) a hydroxy group,    -   (g) a cyano group,    -   (h) a carboxy group,    -   (i) a carbamoyl group,    -   (j) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (k) a C₃₋₁₀ cycloalkyl group (e.g., cyclopentyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a cyano group,    -   (l) an amino group optionally mono- or di-substituted by        substituent(s) selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl),        -   (ii) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl), and        -   (iii) a C₁₋₆ alkoxy-carbonyl group (e.g.,            tert-butoxycarbonyl),    -   (m) an imino group optionally substituted by a hydroxy group,        and    -   (n) a 5- or 6-membered monocyclic aromatic heterocyclyloxy group        (e.g., pyrazolyloxy) optionally substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl),-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl,    tetrahydropyranyl, tetrahydrothiopyranyl,    1,1-dioxidotetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl,    imidazolidinyl, tetrahydrofuryl, 1,1-dioxidotetrahydrothienyl,    morpholinyl, dihydrooxazolyl (2,3-dihydrooxazolyl), dihydrothiazolyl    (2,3-dihydrothiazolyl), piperazinyl, dihydrooxadiazolyl    (4,5-dihydro-1,2,4-oxadiazolyl)) optionally substituted by 1 to 3    substituents selected from    -   (a) an oxo group,    -   (b) a hydroxy group,    -   (c) a cyano group,    -   (d) a halogen atom (e.g., a fluorine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl), and    -   (g) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl),-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl, furyl, pyridyl, imidazolyl (1H-imidazolyl), pyrazolyl,    thienyl, triazolyl (1,2,4-triazolyl), oxazolyl, thiazolyl,    oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted by 1 to 3    substituents selected from    -   (a) a hydroxy group,    -   (b) a cyano group,    -   (c) a carboxy group,    -   (d) a halogen atom (e.g., a fluorine atom, a bromine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (h) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl-carbonyl group(s) (e.g., acetyl),-   (4) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl) optionally substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a hydroxy group,    -   (c) an oxo group,    -   (d) a cyano group,    -   (e) a carboxy group, and    -   (f) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,-   (5) a C₂₋₆ alkenyl group (e.g., allyl) optionally substituted by 1    to 3 substituents selected from    -   (a) a carbamoyl group, and    -   (b) a hydroxy group,-   (6) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to    3 hydroxy groups,-   (7) a 9- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) non-aromatic heterocyclic group (e.g., indolinyl,    dihydrobenzoxadinyl (2,3-dihydro-1,4-benzoxadinyl),    tetrahydroquinolyl (e.g., 1,2,3,4-tetrahydroquinolyl)) optionally    substituted by 1 to 3 oxo groups,-   (8) a 8- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) aromatic heterocyclic group (e.g., pyrrolopyridyl    (pyrrolo[2,3-b]pyridyl), pyrazolopyridyl    (1H-pyrazolo[3,4-b]pyridyl)),-   (9) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl),-   (10) a 5- to 14-membered spiro heterocyclic group (e.g.,    2-oxa-6-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl),-   (11) a 3- to 8-membered monocyclic non-aromatic heterocyclyloxy    group (e.g., oxetanyloxy),-   (12) a C₁₋₆alkoxy group (e.g., methoxy, ethoxy) optionally    substituted by 1 to 3 substituents selected from    -   (a) a C₆₋₁₄ aryl group (e.g., phenyl), and    -   (b) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., oxetanyl), or-   (13) an amino group optionally mono- or di-substituted by    substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., ethyl, isobutyl) optionally        substituted by 1 to 3 hydroxy groups, and    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridazinyl).

In one embodiment, R⁴ is not a methyl group substituted bysubstituent(s) selected from

-   -   (1) an amino group,    -   (2) a mono-substituted amino group (e.g., a mono-C₁₋₆ alkylamino        group, a mono-C₆₋₁₄ arylamino group, a C₇₋₁₆ aralkylamino group,        a 5- to 14-membered aromatic heterocyclylamino group, a C₇₋₁₆        aralkylamino group, a formylamino group, a C₁₋₆        alkyl-carbonylamino group, a C₆₋₁₄ aryl-carbonylamino group, a        C₁₋₆ alkoxy-carbonylamino group, a C₇₋₁₆        aralkyloxy-carbonylamino group, a C₁₋₆ alkylsulfonylamino group,        a C₆₋₁₄ arylsulfonylamino group optionally substituted by C₁₋₆        alkyl group(s)),    -   (3) a di-substituted amino group (e.g., a di-C₁₋₆ alkylamino        group, a di-C₆₋₁₄ arylamino group, a (C₁₋₆ alkyl) (C₁₋₆        alkyl-carbonyl) amino group),    -   (4) an azaheterocyclic group (e.g., a group containing at least        one nitrogen atom as a ring constituting atom, from among a 5-        to 14-membered aromatic heterocyclic group and a 3- to        14-membered non-aromatic heterocyclic group),    -   (5) a hydroxy group,    -   (6) a C₁₋₆ alkoxy group, and    -   (7) a C₁₋₆ alkylsulfanyl group.

In another embodiment, R⁴ is preferably

-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,    butyl, isobutyl, tert-butyl) optionally substituted by 1 to 7    substituents selected from    -   (a) a 3- to 8-membered monocyclic oxygen-containing non-aromatic        heterocyclic group (e.g., tetrahydropyranyl, tetrahydrofuryl),    -   (b) a 5- or 6-membered monocyclic sulfur-containing aromatic        heterocyclic group (e.g., thienyl),    -   (c) a halogen atom (e.g., a fluorine atom),    -   (d) a cyano group,    -   (e) a carboxy group,    -   (f) a carbamoyl group,    -   (g) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (h) a C₃₋₁₀ cycloalkyl group (e.g., cyclopentyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a cyano group,    -   (i) an imino group optionally substituted by a hydroxy group,        and    -   (j) a 5- or 6-membered monocyclic aromatic heterocyclyloxy group        (e.g., pyrazolyloxy) optionally substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl),-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl,    tetrahydropyranyl, tetrahydrothiopyranyl,    1,1-dioxidotetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl,    imidazolidinyl, tetrahydrofuryl, 1,1-dioxidotetrahydrothienyl,    morpholinyl, dihydrooxazolyl (2,3-dihydrooxazolyl), dihydrothiazolyl    (2,3-dihydrothiazolyl), piperazinyl, dihydrooxadiazolyl    (4,5-dihydro-1,2,4-oxadiazolyl)) optionally substituted by 1 to 3    substituents selected from    -   (a) an oxo group,    -   (b) a hydroxy group,    -   (c) a cyano group,    -   (d) a halogen atom (e.g., a fluorine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl), and    -   (g) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl),-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl, furyl, pyridyl, imidazolyl (1H-imidazolyl), pyrazolyl,    thienyl, triazolyl (1,2,4-triazolyl), oxazolyl, thiazolyl,    oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted by 1 to 3    substituents selected from    -   (a) a hydroxy group,    -   (b) a cyano group,    -   (c) a carboxy group,    -   (d) a halogen atom (e.g., a fluorine atom, a bromine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (h) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl-carbonyl group(s) (e.g., acetyl),-   (4) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl) optionally substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a hydroxy group,    -   (c) an oxo group,    -   (d) a cyano group,    -   (e) a carboxy group, and    -   (f) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,-   (5) a C₂₋₆ alkenyl group (e.g., allyl) optionally substituted by 1    to 3 substituents selected from    -   (a) a carbamoyl group, and    -   (b) a hydroxy group,-   (6) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to    3 hydroxy groups,-   (7) a 9- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) non-aromatic heterocyclic group (e.g., indolinyl,    dihydrobenzoxadinyl (2,3-dihydro-1,4-benzoxadinyl),    tetrahydroquinolyl (e.g., 1,2,3,4-tetrahydroquinolyl)) optionally    substituted by 1 to 3 oxo groups,-   (8) a 8- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) aromatic heterocyclic group (e.g., pyrrolopyridyl    (pyrrolo[2,3-b]pyridyl), pyrazolopyridyl    (1H-pyrazolo[3,4-b]pyridyl)),-   (9) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl),-   (10) a 5- to 14-membered spiro heterocyclic group (e.g.,    2-oxa-6-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl),-   (11) a 3- to 8-membered monocyclic non-aromatic heterocyclyloxy    group (e.g., oxetanyloxy),-   (12) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) optionally    substituted by 1 to 3 substituents selected from    -   (a) a C₆₋₁₄ aryl group (e.g., phenyl), and    -   (b) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., oxetanyl), or-   (13) an amino group optionally mono- or di-substituted by    substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., ethyl, isobutyl) optionally        substituted by 1 to 3 hydroxy groups, and    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridazinyl).

Examples of the “3- to 8-membered monocyclic oxygen-containingnon-aromatic heterocyclic group” that the “C₁₋₆ alkyl group”, which isexemplified as the “substituent” represented by R⁴, has include anon-aromatic heterocyclic group containing at least one oxygen atom as aring constituting atom and not containing a nitrogen atom as a ringconstituting atom, from among the above-mentioned “3- to 8-memberedmonocyclic non-aromatic heterocyclic group”.

Examples of the “sulfur-containing heterocyclic group” that the “C₁₋₆alkyl group”, which is exemplified as the “substituent” represented byR⁴, has include a heterocyclic group containing at least one sulfur atomas a ring constituting atom and not containing a nitrogen atom as a ringconstituting atom, from among the above-mentioned “heterocyclic group”.

In one embodiment, when R⁴ is an optionally substituted methyl group,then R⁴ is preferably a methyl group having substituent(s). In anotherembodiment, R⁴ is preferably not a methyl group.

In another embodiment, when R⁴ is a cyclic group (e.g., a C₆₋₁₄ arylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group or aheterocyclic group), then R⁴ is preferably not a 6-memberednitrogen-containing heterocyclic group having an oxo group at thep-position.

In another embodiment, R⁴ is preferably

-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,    butyl, isobutyl, tert-butyl) optionally substituted by 1 to 7    substituents selected from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyrimidinyl (1,6-dihydropyrimidinyl),        dihydropyridyl (1,2-dihydropyridyl, 1,4-dihydropyridyl),        tetrahydropyrimidinyl (1,2,3,4-tetrahydropyrimidinyl),        dihydropyridazinyl (1,4-dihydropyridazinyl,        2,3-dihydropyridazinyl), imidazolidinyl, tetrahydropyranyl,        morpholinyl, piperidyl, dihydrooxadiazolyl        (4,5-dihydro-1,2,4-oxadiazolyl), pyrrolidinyl, tetrahydrofuryl,        piperazinyl, thiazolidinyl, oxazolidinyl, azetidinyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) an oxo group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),        -   (iii) a hydroxy group, and        -   (iv) a cyano group,    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl), isoxazolyl, pyrazolyl,        pyridyl, imidazolyl (1H-imidazolyl), thienyl, tetrazolyl        (1H-tetrazolyl)) optionally substituted by 1 to 3 substituents        selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally            substituted by 1 to 3 substituents selected from a halogen            atom (e.g., a fluorine atom) and a C₆₋₁₄ aryl group (e.g.,            phenyl),        -   (ii) a hydroxy group, and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),    -   (c) a 8- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) aromatic heterocyclic group (e.g., indazolyl        (1H-indazolyl), benzisoxazolyl (benzo[d]isoxazolyl),        benzimidazolyl (1H-benzimidazolyl)),    -   (d) a 9- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) non-aromatic heterocyclic group (e.g.,        dihydrobenzoxazolyl(2,3-dihydrobenzoxazolyl)) optionally        substituted by 1 to 3 oxo groups,    -   (e) a halogen atom (e.g., a fluorine atom),    -   (f) a hydroxy group,    -   (g) a cyano group,    -   (h) a carboxy group,    -   (i) a carbamoyl group,    -   (j) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (k) a C₃₋₁₀ cycloalkyl group (e.g., cyclopentyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a cyano group,    -   (l) an amino group optionally mono- or di-substituted by        substituent(s) selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl),        -   (ii) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl), and        -   (iii) a C₁₋₆alkoxy-carbonyl group (e.g.,            tert-butoxycarbonyl),    -   (m) an imino group optionally substituted by a hydroxy group,        and    -   (n) a 5- or 6-membered monocyclic aromatic heterocyclyloxy group        (e.g., pyrazolyloxy) optionally substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl),-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl,    tetrahydropyranyl, tetrahydrothiopyranyl,    1,1-dioxidotetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl,    imidazolidinyl, tetrahydrofuryl, 1,1-dioxidotetrahydrothienyl,    morpholinyl, dihydrooxazolyl (2,3-dihydrooxazolyl), dihydrothiazolyl    (2,3-dihydrothiazolyl), piperazinyl, dihydrooxadiazolyl    (4,5-dihydro-1,2,4-oxadiazolyl), pyrrolyl (2H-pyrrolyl)) optionally    substituted by 1 to 3 substituents selected from    -   (a) an oxo group,    -   (b) a hydroxy group,    -   (c) a cyano group,    -   (d) a halogen atom (e.g., a fluorine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),    -   (g) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl), and    -   (h) a C₁₋₆ alkylidene group (e.g., methylidene (═CH₂))        optionally substituted by 5- or 6-membered monocyclic aromatic        heterocyclic group(s) (e.g., pyrrolyl (1H-pyrrolyl)) optionally        substituted by 1 to 3 substituents selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl), and        -   (ii) a halogenated boryl group (e.g., difluoroboryl),-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl, furyl, pyridyl, imidazolyl (1H-imidazolyl), pyrazolyl,    thienyl, triazolyl (1,2,4-triazolyl), oxazolyl, thiazolyl,    oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted by 1 to 3    substituents selected from    -   (a) a hydroxy group,    -   (b) a cyano group,    -   (c) a carboxy group,    -   (d) a halogen atom (e.g., a fluorine atom, a bromine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (h) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl-carbonyl group(s) (e.g., acetyl),-   (4) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl) optionally substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a hydroxy group,    -   (c) an oxo group,    -   (d) a cyano group,    -   (e) a carboxy group, and    -   (f) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,-   (5) a C₂₋₆ alkenyl group (e.g., allyl) optionally substituted by 1    to 3 substituents selected from    -   (a) a carbamoyl group, and    -   (b) a hydroxy group,-   (6) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to    3 hydroxy groups,-   (7) a 9- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) non-aromatic heterocyclic group (e.g., indolinyl,    dihydrobenzoxadinyl (2,3-dihydro-1,4-benzoxadinyl),    tetrahydroquinolyl (e.g., 1,2,3,4-tetrahydroquinolyl)) optionally    substituted by 1 to 3 oxo groups,-   (8) a 8- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) aromatic heterocyclic group (e.g., pyrrolopyridyl    (pyrrolo[2,3-b]pyridyl), pyrazolopyridyl    (1H-pyrazolo[3,4-b]pyridyl)),-   (9) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl),-   (10) a 5- to 14-membered spiro heterocyclic group (e.g.,    2-oxa-6-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl),-   (11) a 3- to 8-membered monocyclic non-aromatic heterocyclyloxy    group (e.g., oxetanyloxy), or-   (12) an amino group optionally mono- or di-substituted by    substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., ethyl, isobutyl) optionally        substituted by 1 to 3 hydroxy groups, and    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridazinyl).

R⁴ is more preferably

-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isobutyl)    optionally substituted by 1 to 7 substituents selected from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyrimidinyl (1,6-dihydropyrimidinyl),        dihydropyridyl (1,2-dihydropyridyl, 1,4-dihydropyridyl),        dihydropyridazinyl (1,4-dihydropyridazinyl,        2,3-dihydropyridazinyl), imidazolidinyl, tetrahydropyranyl,        morpholinyl, piperidyl, tetrahydropyrimidinyl        (1,2,3,4-tetrahydropyrimidinyl)) optionally substituted by 1 to        3 substituents selected from        -   (i) an oxo group, and        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl), isoxazolyl, pyrazolyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl), and        -   (ii) a hydroxy group,    -   (c) a 8- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) aromatic heterocyclic group (e.g., indazolyl        (1H-indazolyl), benzimidazolyl (1H-benzimidazolyl)),    -   (d) a halogen atom (e.g., a fluorine atom),    -   (e) a hydroxy group,    -   (f) a cyano group,    -   (g) a carboxy group,    -   (h) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl), and    -   (i) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl-carbonyl group(s) (e.g., acetyl),-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl,    tetrahydropyranyl) optionally substituted by 1 to 3 substituents    selected from    -   (a) an oxo group,    -   (b) a hydroxy group,    -   (c) a halogen atom (e.g., a fluorine atom), and    -   (d) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl),-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,-   (4) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl)    optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine    atom), or-   (5) an amino group optionally mono- or di-substituted by C₁₋₆ alkyl    group(s) (e.g., ethyl).

R⁴ is further more preferably

-   (1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 5-    or 6-membered monocyclic aromatic heterocyclic group(s) (e.g.,    isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl) optionally substituted by 1 to 3 oxo groups, or-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl) optionally substituted by 1 to 3 hydroxy groups.

In another embodiment, R⁴ is preferably

-   (1) an optionally substituted 5-membered heterocyclic group,-   (2) an optionally substituted 6-membered non-aromatic heterocyclic    group,-   (3) an optionally substituted 4-membered non-aromatic heterocyclic    group,-   (4) an optionally substituted C₃₋₄ cycloalkyl group, or-   (5) an optionally substituted C₁₋₆ alkyl group.

Examples of the “5-membered heterocyclic group” of the “optionallysubstituted 5-membered heterocyclic group” represented by R⁴ include a5-membered group, from among the above-mentioned “heterocyclic group”.The “5-membered heterocyclic group” is optionally substituted, forexample, by substituent(s) selected from the above-mentioned SubstituentGroup C. The number of the substituents is, for example, 1 to 3. Whenthe number of the substituents is 2 or more, the respective substituentsmay be the same or different.

Examples of the “6-membered non-aromatic heterocyclic group” of the“optionally substituted 6-membered non-aromatic heterocyclic group”represented by R⁴ include a 6-membered group, from among theabove-mentioned “3- to 8-membered monocyclic non-aromatic heterocyclicgroup”. The “6-membered non-aromatic heterocyclic group” is optionallyfurther substituted, for example, by substituent(s) selected from theabove-mentioned Substituent Group C. The number of the substituents is,for example, 1 to 3. When the number of the substituents is 2 or more,the respective substituents may be the same or different.

Examples of the “4-membered non-aromatic heterocyclic group” of the“optionally substituted 4-membered non-aromatic heterocyclic group”represented by R⁴ include a 4-membered group, from among theabove-mentioned “3- to 8-membered monocyclic non-aromatic heterocyclicgroup”. The “4-membered non-aromatic heterocyclic group” is optionallyfurther substituted, for example, by substituent(s) selected from theabove-mentioned Substituent Group C. The number of the substituents is,for example, 1 to 3. When the number of the substituents is 2 or more,the respective substituents may be the same or different.

Examples of the “C₃₋₄ cycloalkyl group” of the “optionally substitutedC₃₋₄ cycloalkyl group” represented by R⁴ include cyclopropyl andcyclobutyl. The “C₃₋₄ cycloalkyl group” is optionally furthersubstituted, for example, by substituent(s) selected from theabove-mentioned Substituent Group A. The number of the substituents is,for example, 1 to 3. When the number of the substituents is 2 or more,the respective substituents may be the same or different.

Examples of the “C₁₋₄ alkyl group” of the “optionally substituted C₁₋₄alkyl group” represented by R⁴ include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl and tert-butyl. The “C₁₋₄ alkyl group” isoptionally further substituted, for example, by substituent(s) selectedfrom the above-mentioned Substituent Group B. The number of thesubstituents is, for example, 1 to 3. When the number of thesubstituents is 2 or more, the respective substituents may be the sameor different.

R⁴ is more preferably

-   (1) a 5-membered heterocyclic group (e.g., isoxazolyl, pyrrolidinyl,    oxazolidinyl) optionally substituted by 1 to 3 substituents selected    from    -   (a) a hydroxy group,    -   (b) an oxo group, and    -   (c) a halogen atom (e.g., a fluorine atom),-   (2) a 6-membered non-aromatic heterocyclic group (e.g., piperidyl,    tetrahydropyranyl) optionally substituted by 1 to 3 C₁₋₆    alkyl-carbonyl groups,-   (3) a 4-membered non-aromatic heterocyclic group (e.g., azetidinyl)    optionally substituted by 1 to 3 hydroxy groups,-   (4) a C₃₋₄ cycloalkyl group optionally substituted by 1 to 3 halogen    atoms (e.g., a fluorine atom), or-   (5) a C₁₋₄ alkyl group (e.g., methyl, ethyl, propyl, isobutyl)    optionally substituted by 1 to 7 substituents selected from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyrimidinyl (1,6-dihydropyrimidinyl),        dihydropyridyl (1,2-dihydropyridyl, 1,4-dihydropyridyl),        dihydropyridazinyl (1,4-dihydropyridazinyl,        2,3-dihydropyridazinyl), imidazolidinyl, tetrahydropyranyl,        morpholinyl, piperidyl) optionally substituted by 1 to 3        substituents selected from        -   (i) an oxo group, and        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl), isoxazolyl, pyrazolyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl), and        -   (ii) a hydroxy group,    -   (c) a 8- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) aromatic heterocyclic group (e.g., indazolyl        (1H-indazolyl), benzimidazolyl (1H-benzimidazolyl)),    -   (d) a halogen atom (e.g., a fluorine atom),    -   (e) a hydroxy group,    -   (f) a cyano group,    -   (g) a carboxy group,    -   (h) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl), and    -   (i) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl-carbonyl group(s) (e.g., acetyl).

R⁴ is further more preferably

-   (1) a 5-membered heterocyclic group (e.g., isoxazolyl, pyrrolidinyl)    optionally substituted by 1 to 3 substituents selected from    -   (a) a hydroxy group, and    -   (b) an oxo group, or-   (2) a C₁₋₄ alkyl group (e.g., methyl) optionally substituted by 5-    or 6-membered monocyclic aromatic heterocyclic group(s) (e.g.,    isoxazolyl) optionally substituted by 1 to 3 hydroxy groups.

In another embodiment, R⁴ is preferably

-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,    butyl, isobutyl, tert-butyl) optionally substituted by 1 to 7    substituents selected from    -   (a) a 3- to 8-membered monocyclic oxygen-containing non-aromatic        heterocyclic group (e.g., tetrahydropyranyl, tetrahydrofuryl),    -   (b) a 5- or 6-membered monocyclic sulfur-containing aromatic        heterocyclic group (e.g., thienyl),    -   (c) a halogen atom (e.g., a fluorine atom),    -   (d) a cyano group,    -   (e) a carboxy group,    -   (f) a carbamoyl group,    -   (g) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (h) a C₃₋₁₀ cycloalkyl group (e.g., cyclopentyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a cyano group,    -   (i) an imino group optionally substituted by a hydroxy group,        and    -   (j) a 5- or 6-membered monocyclic aromatic heterocyclyloxy group        (e.g., pyrazolyloxy) optionally substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl),-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl,    tetrahydropyranyl, tetrahydrothiopyranyl,    1,1-dioxidotetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl,    imidazolidinyl, tetrahydrofuryl, 1,1-dioxidotetrahydrothienyl,    morpholinyl, dihydrooxazolyl (2,3-dihydrooxazolyl), dihydrothiazolyl    (2,3-dihydrothiazolyl), piperazinyl, dihydrooxadiazolyl    (4,5-dihydro-1,2,4-oxadiazolyl), pyrrolyl (2H-pyrrolyl)) optionally    substituted by 1 to 3 substituents selected from    -   (a) an oxo group,    -   (b) a hydroxy group,    -   (c) a cyano group,    -   (d) a halogen atom (e.g., a fluorine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),    -   (g) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl), and    -   (h) a C₁₋₆ alkylidene group (e.g., methylidene (═CH₂))        optionally substituted by 5- or 6-membered monocyclic aromatic        heterocyclic group(s) (e.g., pyrrolyl (1H-pyrrolyl)) optionally        substituted by 1 to 3 substituents selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl), and        -   (ii) a halogenated boryl group (e.g., difluoroboryl),-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl, furyl, pyridyl, imidazolyl (1H-imidazolyl), pyrazolyl,    thienyl, triazolyl (1,2,4-triazolyl), oxazolyl, thiazolyl,    oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted by 1 to 3    substituents selected from    -   (a) a hydroxy group,    -   (b) a cyano group,    -   (c) a carboxy group,    -   (d) a halogen atom (e.g., a fluorine atom, a bromine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (h) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl-carbonyl group(s) (e.g., acetyl),-   (4) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl) optionally substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a hydroxy group,    -   (c) an oxo group,    -   (d) a cyano group,    -   (e) a carboxy group, and    -   (f) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,-   (5) a C₂₋₆ alkenyl group (e.g., allyl) optionally substituted by 1    to 3 substituents selected from    -   (a) a carbamoyl group, and    -   (b) a hydroxy group,-   (6) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to    3 hydroxy groups,-   (7) a 9- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) non-aromatic heterocyclic group (e.g., indolinyl,    dihydrobenzoxadinyl (2,3-dihydro-1,4-benzoxadinyl),    tetrahydroquinolyl (e.g., 1,2,3,4-tetrahydroquinolyl)) optionally    substituted by 1 to 3 oxo groups,-   (8) a 8- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) aromatic heterocyclic group (e.g., pyrrolopyridyl    (pyrrolo[2,3-b]pyridyl), pyrazolopyridyl    (1H-pyrazolo[3,4-b]pyridyl)),-   (9) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl),-   (10) a 5- to 14-membered spiro heterocyclic group (e.g.,    2-oxa-6-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl),-   (11) a 3- to 8-membered monocyclic non-aromatic heterocyclyloxy    group (e.g., oxetanyloxy), or-   (12) an amino group optionally mono- or di-substituted by    substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., ethyl, isobutyl) optionally        substituted by 1 to 3 hydroxy groups, and    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridazinyl).

R⁴ is more preferably

-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isobutyl)    optionally substituted by 1 to 7 substituents selected from    -   (a) a 3- to 8-membered monocyclic oxygen-containing non-aromatic        heterocyclic group (e.g., tetrahydropyranyl),    -   (b) a halogen atom (e.g., a fluorine atom),    -   (c) a cyano group,    -   (d) a carboxy group, and    -   (e) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl,    tetrahydropyranyl) optionally substituted by 1 to 3 substituents    selected from    -   (a) an oxo group,    -   (b) a hydroxy group,    -   (c) a halogen atom (e.g., a fluorine atom), and    -   (d) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl),-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,-   (4) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl)    optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine    atom), or-   (5) an amino group optionally mono- or di-substituted by C₁₋₆ alkyl    group(s) (e.g., ethyl).

R⁴ is further more preferably

-   (1) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl) optionally substituted by 1 to 3 oxo groups, or-   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl) optionally substituted by 1 to 3 hydroxy groups.

Or When R³ is a substituent, then preferably R³ and R⁴ in combinationoptionally form, together with the nitrogen atom adjacent to R³ and thecarbon atom adjacent to R⁴, a 3- to 14-membered non-aromatic heterocycle(containing a spiro ring) (e.g., pyrrolidine, 2,7-diazaspiro[4.4]nonane)substituted by one oxo group and optionally further substituted by 1 to3 oxo groups.

In one embodiment, preferably R³ and R⁴ in combination do not form aring, together with the nitrogen atom adjacent to R and the carbon atomadjacent to R⁴.

Preferable examples of the ring, group, substituent and the likeexplained in the present specification are more preferably used incombination.

Preferable examples of compounds (I), (I′) and (I″) include thefollowing compounds.

Provided that, in preferable compounds (I) or (I′),α-(acetylamino)-N-[4-(1,1-dimethylethyl)phenyl]-cyclopentaneacetamide isexcluded from the compound, and a group represented by the formula:

-   -   wherein    -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a        substituent, or a nitrogen atom,    -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a        substituent, or a nitrogen atom,    -   A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a        substituent, or a nitrogen atom, or    -   when A² is CR^(A2) wherein R^(A2) is a substituent, and A³ is        CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and R^(A3)        in combination optionally form, together with the carbon atoms        that they are bonded to, a hydrocarbon ring or a heterocycle,    -   R⁹ is a hydrogen atom or a hydroxy group, and when R⁹ is a        hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and        CR^(A), respectively, and    -   R¹⁰ is a hydroxy group or an optionally substituted C₁₋₆ alkoxy        group,        is excluded from R⁴, and        moreover, in preferable compounds (I), in addition to the        above-mentioned exclusions,

-   (1) a cyclic group represented by the formula:

-   -   wherein X is CH or a nitrogen atom, which is optionally further        substituted, and

-   (2) a cyclic group represented by the formula:

are excluded from the ring formed by R³ and R⁴ in combination togetherwith the nitrogen atom adjacent to R³ and the carbon atom adjacent toR⁴.

In preferable compound (I″),α-(acetylamino)-N-[4-(1,1-dimethylethyl)phenyl]-cyclopentaneacetamide isexcluded from the compound, and a group represented by the formula:

-   -   wherein    -   A¹ is CR^(A1) wherein R^(A1) is a hydrogen atom or a        substituent, or a nitrogen atom,    -   A² is CR^(A2) wherein R^(A2) is a hydrogen atom or a        substituent, or a nitrogen atom,    -   A³ is CR^(A3) wherein R^(A3) is a hydrogen atom or a        substituent, or a nitrogen atom, or    -   when A² is CR^(A2) wherein R^(A2) is a substituent, and A³ is        CR^(A3) wherein R^(A3) is a substituent, then R^(A2) and R^(A3)        in combination optionally form, together with the carbon atoms        that they are bonded to, a hydrocarbon ring or a heterocycle,        and    -   R⁹ is a hydrogen atom or a hydroxy group, and when R⁹ is a        hydroxy group, then A¹, A² and A³ are CR^(A1), CR^(A2) and        CR^(A), respectively,        is excluded from R⁴.        [Compound A-1]

A compound wherein

Ring A is a 6-membered aromatic ring (preferably a benzene ring)optionally further substituted by 1 to 3 substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (2) a cyano group;        R¹ is

-   (1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   Q is a carbon atom, a silicon atom or a germanium atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (b) a hydroxy group,    -   (c) a C₆₋₁₄ aryl group (e.g., phenyl),    -   (d) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (e) a cyano group,    -   (f) a carbamoyl group optionally mono- or di-substituted by        C₃₋₁₀ cycloalkyl group(s) (e.g., cyclopropyl), or    -   (g) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or        R^(1a) and R^(1b) in combination form, together with the        adjacent Q a C₃₋₁₀ cycloalkane ring (e.g., cyclopentane),

-   (2) a neopentyl group, or

-   (3) a trimethylsilylmethyl group;    R² is

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is    -   (A) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (a) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy)            optionally substituted by 1 to 3 substituents selected from            -   (i) a halogen atom (e.g., a fluorine atom), and            -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy), and        -   (b) a hydroxy group, or    -   (B) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy)        optionally substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g.,        methoxy), and    -   the benzene ring in the formula optionally has, besides R⁵,        additional 1 to 3 substituents selected from        -   (A) a C₁₋₆ alkyl group (e.g., methyl), and        -   (B) a C₁₋₆ alkoxy group (e.g., methoxy),

-   (2) a bicyclic fused heterocyclic group (e.g., dihydrobenzofuryl    (2,3-dihydrobenzofuryl), indazolyl (1H-indazolyl, 2H-indazolyl),    indolyl, indolinyl) optionally substituted by 1 to 3 C₁₋₆ alkyl    groups (e.g., methyl), or

-   (3) a group represented by the formula -L-Z¹:    -   wherein    -   L is a bond; and    -   Z¹ is    -   (A) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally        substituted by 1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom), and        -   (b) a hydroxy group, or    -   (B) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, piperidyl,        1,1-dioxidotetrahydrothiopyranyl) optionally substituted by C₁₋₆        alkyl group(s) (e.g., ethyl) optionally substituted by 1 to 3        halogen atoms (e.g., a fluorine atom);        R³ is

-   (1) a hydrogen atom, or

-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted    by 1 to 3 cyano groups; and    R⁴ is

-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,    butyl, isobutyl, tert-butyl) optionally substituted by 1 to 7    substituents selected from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyrimidinyl (1,6-dihydropyrimidinyl),        dihydropyridyl (1,2-dihydropyridyl, 1,4-dihydropyridyl),        tetrahydropyrimidinyl (1,2,3,4-tetrahydropyrimidinyl),        dihydropyridazinyl (1,4-dihydropyridazinyl,        2,3-dihydropyridazinyl), imidazolidinyl, tetrahydropyranyl,        morpholinyl, piperidyl, dihydrooxadiazolyl        (4,5-dihydro-1,2,4-oxadiazolyl), pyrrolidinyl, tetrahydrofuryl,        piperazinyl, thiazolidinyl, oxazolidinyl, azetidinyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) an oxo group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),        -   (iii) a hydroxy group, and        -   (iv) a cyano group,    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl), isoxazolyl, pyrazolyl,        pyridyl, imidazolyl (1H-imidazolyl), thienyl, tetrazolyl        (1H-tetrazolyl)) optionally substituted by 1 to 3 substituents        selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally            substituted by 1 to 3 substituents selected from a halogen            atom (e.g., a fluorine atom) and a C₆₋₁₄ aryl group (e.g.,            phenyl),        -   (ii) a hydroxy group, and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),    -   (c) a 8- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) aromatic heterocyclic group (e.g., indazolyl        (1H-indazolyl), benzisoxazolyl (benzo[d]isoxazolyl),        benzimidazolyl (1H-benzimidazolyl)),    -   (d) a 9- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) non-aromatic heterocyclic group (e.g.,        dihydrobenzoxazolyl(2,3-dihydrobenzoxazolyl)) optionally        substituted by 1 to 3 oxo groups,    -   (e) a halogen atom (e.g., a fluorine atom),    -   (f) a hydroxy group,    -   (g) a cyano group,    -   (h) a carboxy group,    -   (i) a carbamoyl group,    -   (j) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (k) a C₃₋₁₀ cycloalkyl group (e.g., cyclopentyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a cyano group,    -   (l) an amino group optionally mono- or di-substituted by        substituent(s) selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl),        -   (ii) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl), and        -   (iii) a C₁₋₆ alkoxy-carbonyl group (e.g.,            tert-butoxycarbonyl),    -   (m) an imino group optionally substituted by a hydroxy group,        and    -   (n) a 5- or 6-membered monocyclic aromatic heterocyclyloxy group        (e.g., pyrazolyloxy) optionally substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl),

-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl,    tetrahydropyranyl, tetrahydrothiopyranyl,    1,1-dioxidotetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl,    imidazolidinyl, tetrahydrofuryl, 1,1-dioxidotetrahydrothienyl,    morpholinyl, dihydrooxazolyl (2,3-dihydrooxazolyl), dihydrothiazolyl    (2,3-dihydrothiazolyl), piperazinyl, dihydrooxadiazolyl    (4,5-dihydro-1,2,4-oxadiazolyl), pyrrolyl (2H-pyrrolyl)) optionally    substituted by 1 to 3 substituents selected from    -   (a) an oxo group,    -   (b) a hydroxy group,    -   (c) a cyano group,    -   (d) a halogen atom (e.g., a fluorine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),    -   (g) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl), and    -   (h) a C₁₋₆ alkylidene group (e.g., methylidene (═CH₂))        optionally substituted by 5- or 6-membered monocyclic aromatic        heterocyclic group(s) (e.g., pyrrolyl (1H-pyrrolyl)) optionally        substituted by 1 to 3 substituents selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl), and        -   (ii) a halogenated boryl group (e.g., difluoroboryl),

-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl, furyl, pyridyl, imidazolyl (1H-imidazolyl), pyrazolyl,    thienyl, triazolyl (1,2,4-triazolyl), oxazolyl, thiazolyl,    oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted by 1 to 3    substituents selected from    -   (a) a hydroxy group,    -   (b) a cyano group,    -   (c) a carboxy group,    -   (d) a halogen atom (e.g., a fluorine atom, a bromine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (h) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl-carbonyl group(s) (e.g., acetyl),

-   (4) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl) optionally substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a hydroxy group,    -   (c) an oxo group,    -   (d) a cyano group,    -   (e) a carboxy group, and    -   (f) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,

-   (5) a C₂₋₆ alkenyl group (e.g., allyl) optionally substituted by 1    to 3 substituents selected from    -   (a) a carbamoyl group, and    -   (b) a hydroxy group,

-   (6) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to    3 hydroxy groups,

-   (7) a 9- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) non-aromatic heterocyclic group (e.g., indolinyl,    dihydrobenzoxadinyl (2,3-dihydro-1,4-benzoxadinyl),    tetrahydroquinolyl (e.g., 1,2,3,4-tetrahydroquinolyl)) optionally    substituted by 1 to 3 oxo groups,

-   (8) a 8- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) aromatic heterocyclic group (e.g., pyrrolopyridyl    (pyrrolo[2,3-b]pyridyl), pyrazolopyridyl    (1H-pyrazolo[3,4-b]pyridyl)),

-   (9) a C₁₋₁₂ alkoxy-carbonyl group (e.g., ethoxycarbonyl),

-   (10) a 5- to 14-membered spiro heterocyclic group (e.g.,    2-oxa-6-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl),

-   (11) a 3- to 8-membered monocyclic non-aromatic heterocyclyloxy    group (e.g., oxetanyloxy), or

-   (12) an amino group optionally mono- or di-substituted by    substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., ethyl, isobutyl) optionally        substituted by 1 to 3 hydroxy groups, and    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridazinyl); or        when R³ is a substituent, R³ and R⁴ in combination form,        together with the nitrogen atom adjacent to R³ and the carbon        atom adjacent to R⁴, a 3- to 14-membered non-aromatic        heterocycle (containing a spiro ring) (e.g., pyrrolidine,        2,7-diazaspiro[4.4]nonane) substituted by one oxo group and        optionally further substituted by 1 to 3 oxo groups, or a salt        thereof.        [Compound A-2]

A compound wherein

Ring A is a 6-membered aromatic ring (preferably a benzene ring)optionally further substituted by 1 to 3 substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (2) a cyano group;        R¹ is

-   (1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   Q is a carbon atom, a silicon atom or a germanium atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (b) a hydroxy group,    -   (c) a C₆₋₁₄ aryl group (e.g., phenyl),    -   (d) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (e) a cyano group,    -   (f) a carbamoyl group optionally mono- or di-substituted by        C₃₋₁₀ cycloalkyl group(s) (e.g., cyclopropyl), or    -   (g) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or        R^(1a) and R^(1b) in combination form, together with the        adjacent Q, a C₃₋₁₀ cycloalkane ring (e.g., cyclopentane),

-   (2) a neopentyl group, or

-   (3) a trimethylsilylmethyl group;    R² is

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is    -   (A) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (a) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy)            optionally substituted by 1 to 3 substituents selected from            -   (i) a halogen atom (e.g., a fluorine atom), and            -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy), and        -   (b) a hydroxy group, or    -   (B) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy)        optionally substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g.,        methoxy), and    -   the benzene ring in the formula optionally has, besides R⁵,        additional 1 to 3 substituents selected from        -   (A) a C₁₋₆ alkyl group (e.g., methyl), and        -   (B) a C₁₋₆ alkoxy group (e.g., methoxy),

-   (2) a bicyclic fused heterocyclic group (e.g., dihydrobenzofuryl    (2,3-dihydrobenzofuryl), indazolyl (1H-indazolyl, 2H-indazolyl),    indolyl, indolinyl) optionally substituted by 1 to 3 C₁₋₆ alkyl    groups (e.g., methyl), or

-   (3) a group represented by the formula -L-Z¹:    -   wherein    -   L is a bond; and    -   Z¹ is    -   (A) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally        substituted by 1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom), and        -   (b) a hydroxy group, or    -   (B) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, piperidyl,        1,1-dioxidotetrahydrothiopyranyl) optionally substituted by C₁₋₆        alkyl group(s) (e.g., ethyl) optionally substituted by 1 to 3        halogen atoms (e.g., a fluorine atom);        R³ is

-   (1) a hydrogen atom, or

-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted    by 1 to 3 cyano groups; and    R⁴ is

-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,    butyl, isobutyl, tert-butyl) optionally substituted by 1 to 7    substituents selected from    -   (a) a 3- to 8-membered monocyclic oxygen-containing non-aromatic        heterocyclic group (e.g., tetrahydropyranyl, tetrahydrofuryl),    -   (b) a 5- or 6-membered monocyclic sulfur-containing aromatic        heterocyclic group (e.g., thienyl),    -   (c) a halogen atom (e.g., a fluorine atom),    -   (d) a cyano group,    -   (e) a carboxy group,    -   (f) a carbamoyl group,    -   (g) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (h) a C₃₋₁₀ cycloalkyl group (e.g., cyclopentyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a cyano group,    -   (i) an imino group optionally substituted by a hydroxy group,        and    -   (j) a 5- or 6-membered monocyclic aromatic heterocyclyloxy group        (e.g., pyrazolyloxy) optionally substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl),

-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl,    tetrahydropyranyl, tetrahydrothiopyranyl,    1,1-dioxidotetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl,    imidazolidinyl, tetrahydrofuryl, 1,1-dioxidotetrahydrothienyl,    morpholinyl, dihydrooxazolyl (2,3-dihydrooxazolyl), dihydrothiazolyl    (2,3-dihydrothiazolyl), piperazinyl, dihydrooxadiazolyl    (4,5-dihydro-1,2,4-oxadiazolyl), pyrrolyl (2H-pyrrolyl)) optionally    substituted by 1 to 3 substituents selected from    -   (a) an oxo group,    -   (b) a hydroxy group,    -   (c) a cyano group,    -   (d) a halogen atom (e.g., a fluorine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),    -   (g) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl), and    -   (h) a C₁₋₆ alkylidene group (e.g., methylidene (═CH₂))        optionally substituted by 5- or 6-membered monocyclic aromatic        heterocyclic group(s) (e.g., pyrrolyl (1H-pyrrolyl)) optionally        substituted by 1 to 3 substituents selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl), and        -   (ii) a halogenated boryl group (e.g., difluoroboryl),

-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl, furyl, pyridyl, imidazolyl (1H-imidazolyl), pyrazolyl,    thienyl, triazolyl (1,2,4-triazolyl), oxazolyl, thiazolyl,    oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted by 1 to 3    substituents selected from    -   (a) a hydroxy group,    -   (b) a cyano group,    -   (c) a carboxy group,    -   (d) a halogen atom (e.g., a fluorine atom, a bromine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (h) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl-carbonyl group(s) (e.g., acetyl),

-   (4) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl) optionally substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a hydroxy group,    -   (c) an oxo group,    -   (d) a cyano group,    -   (e) a carboxy group, and    -   (f) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,

-   (5) a C₂₋₆ alkenyl group (e.g., allyl) optionally substituted by 1    to 3 substituents selected from    -   (a) a carbamoyl group, and    -   (b) a hydroxy group,

-   (6) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to    3 hydroxy groups,

-   (7) a 9- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) non-aromatic heterocyclic group (e.g., indolinyl,    dihydrobenzoxadinyl (2,3-dihydro-1,4-benzoxadinyl),    tetrahydroquinolyl (e.g., 1,2,3,4-tetrahydroquinolyl)) optionally    substituted by 1 to 3 oxo groups,

-   (8) a 8- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) aromatic heterocyclic group (e.g., pyrrolopyridyl    (pyrrolo[2,3-b]pyridyl), pyrazolopyridyl    (1H-pyrazolo[3,4-b]pyridyl)),

-   (9) a C₁₋₁₂ alkoxy-carbonyl group (e.g., ethoxycarbonyl),

-   (10) a 5- to 14-membered spiro heterocyclic group (e.g.,    2-oxa-6-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl),

-   (11) a 3- to 8-membered monocyclic non-aromatic heterocyclyloxy    group (e.g., oxetanyloxy), or

-   (12) an amino group optionally mono- or di-substituted by    substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., ethyl, isobutyl) optionally        substituted by 1 to 3 hydroxy groups, and    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridazinyl); or        when R³ is a substituent, R³ and R⁴ in combination form,        together with the nitrogen atom adjacent to R³ and the carbon        atom adjacent to R⁴, a 3- to 14-membered non-aromatic        heterocycle (containing a spiro ring) (e.g., pyrrolidine,        2,7-diazaspiro[4.4]nonane) substituted by one oxo group and        optionally further substituted by 1 to 3 oxo groups, or a salt        thereof.        [Compound A-3]

A compound wherein

Ring A is a 6-membered aromatic ring (preferably a benzene ring)optionally further substituted by 1 to 3 substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (2) a cyano group;        R¹ is

-   (1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   Q is a carbon atom, a silicon atom or a germanium atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (b) a hydroxy group,    -   (c) a C₆₋₁₄ aryl group (e.g., phenyl),    -   (d) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (e) a cyano group,    -   (f) a carbamoyl group optionally mono- or di-substituted by        C₃₋₁₀ cycloalkyl group(s) (e.g., cyclopropyl), or    -   (g) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or        R^(1a) and R^(1b) in combination form, together with the        adjacent Q, a C₃₋₁₀ cycloalkane ring (e.g., cyclopentane),

-   (2) a neopentyl group, or

-   (3) a trimethylsilylmethyl group;    R² is

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is    -   (A) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (a) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy)            optionally substituted by 1 to 3 substituents selected from            -   (i) a halogen atom (e.g., a fluorine atom), and            -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy), and        -   (b) a hydroxy group, or    -   (B) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy)        optionally substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g.,        methoxy), and the benzene ring in the formula optionally has,        besides R⁵, additional 1 to 3 substituents selected from        -   (A) a C₁₋₆ alkyl group (e.g., methyl), and        -   (B) a C₁₋₆ alkoxy group (e.g., methoxy),

-   (2) a bicyclic fused heterocyclic group (e.g., dihydrobenzofuryl    (2,3-dihydrobenzofuryl), indazolyl (1H-indazolyl, 2H-indazolyl),    indolyl, indolinyl) optionally substituted by 1 to 3 C₁₋₆ alkyl    groups (e.g., methyl), or

-   (3) a group represented by the formula -L-Z¹:    -   wherein    -   L is a bond; and    -   Z¹ is    -   (A) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally        substituted by 1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom), and        -   (b) a hydroxy group, or    -   (B) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, piperidyl,        1,1-dioxidotetrahydrothiopyranyl) optionally substituted by C₁₋₆        alkyl group(s) (e.g., ethyl) optionally substituted by 1 to 3        halogen atoms (e.g., a fluorine atom);        R³ is

-   (1) a hydrogen atom, or

-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted    by 1 to 3 cyano groups; and    R⁴ is

-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,    butyl, isobutyl, tert-butyl) optionally substituted by 1 to 7    substituents selected from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyrimidinyl (1,6-dihydropyrimidinyl),        dihydropyridyl (1,2-dihydropyridyl, 1,4-dihydropyridyl),        tetrahydropyrimidinyl (1,2,3,4-tetrahydropyrimidinyl),        dihydropyridazinyl (1,4-dihydropyridazinyl,        2,3-dihydropyridazinyl), imidazolidinyl, tetrahydropyranyl,        morpholinyl, piperidyl, dihydrooxadiazolyl        (4,5-dihydro-1,2,4-oxadiazolyl), pyrrolidinyl, tetrahydrofuryl,        piperazinyl, thiazolidinyl, oxazolidinyl, azetidinyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) an oxo group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),        -   (iii) a hydroxy group, and        -   (iv) a cyano group,    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl), isoxazolyl, pyrazolyl,        pyridyl, imidazolyl (1H-imidazolyl), thienyl, tetrazolyl        (1H-tetrazolyl)) optionally substituted by 1 to 3 substituents        selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally            substituted by 1 to 3 substituents selected from a halogen            atom (e.g., a fluorine atom) and a C₆₋₁₄ aryl group (e.g.,            phenyl),        -   (ii) a hydroxy group, and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),    -   (c) a 8- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) aromatic heterocyclic group (e.g., indazolyl        (1H-indazolyl), benzisoxazolyl (benzo[d]isoxazolyl),        benzimidazolyl (1H-benzimidazolyl)),    -   (d) a 9- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) non-aromatic heterocyclic group (e.g.,        dihydrobenzoxazolyl(2,3-dihydrobenzoxazolyl)) optionally        substituted by 1 to 3 oxo groups,    -   (e) a halogen atom (e.g., a fluorine atom),    -   (f) a hydroxy group,    -   (g) a cyano group,    -   (h) a carboxy group,    -   (i) a carbamoyl group,    -   (j) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (k) a C₃₋₁₀ cycloalkyl group (e.g., cyclopentyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a cyano group,    -   (l) an amino group optionally mono- or di-substituted by        substituent(s) selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl),        -   (ii) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl), and        -   (iii) a C₁₋₆ alkoxy-carbonyl group (e.g.,            tert-butoxycarbonyl),    -   (m) an imino group optionally substituted by a hydroxy group,        and    -   (n) a 5- or 6-membered monocyclic aromatic heterocyclyloxy group        (e.g., pyrazolyloxy) optionally substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl),

-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl,    tetrahydropyranyl, tetrahydrothiopyranyl,    1,1-dioxidotetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl,    imidazolidinyl, tetrahydrofuryl, 1,1-dioxidotetrahydrothienyl,    morpholinyl, dihydrooxazolyl (2,3-dihydrooxazolyl), dihydrothiazolyl    (2,3-dihydrothiazolyl), piperazinyl, dihydrooxadiazolyl    (4,5-dihydro-1,2,4-oxadiazolyl), pyrrolyl (2H-pyrrolyl)) optionally    substituted by 1 to 3 substituents selected from    -   (a) an oxo group,    -   (b) a hydroxy group,    -   (c) a cyano group,    -   (d) a halogen atom (e.g., a fluorine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),    -   (g) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl), and    -   (h) a C₁₋₆ alkylidene group (e.g., methylidene (═CH₂))        optionally substituted by 5- or 6-membered monocyclic aromatic        heterocyclic group(s) (e.g., pyrrolyl (1H-pyrrolyl)) optionally        substituted by 1 to 3 substituents selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl), and        -   (ii) a halogenated boryl group (e.g., difluoroboryl),

-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl, furyl, pyridyl, imidazolyl (1H-imidazolyl), pyrazolyl,    thienyl, triazolyl (1,2,4-triazolyl), oxazolyl, thiazolyl,    oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted by 1 to 3    substituents selected from    -   (a) a hydroxy group,    -   (b) a cyano group,    -   (c) a carboxy group,    -   (d) a halogen atom (e.g., a fluorine atom, a bromine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (h) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl-carbonyl group(s) (e.g., acetyl),

-   (4) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl) optionally substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a hydroxy group,    -   (c) an oxo group,    -   (d) a cyano group,    -   (e) a carboxy group, and    -   (f) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,

-   (5) a C₂₋₆ alkenyl group (e.g., allyl) optionally substituted by 1    to 3 substituents selected from    -   (a) a carbamoyl group, and    -   (b) a hydroxy group,

-   (6) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to    3 hydroxy groups,

-   (7) a 9- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) non-aromatic heterocyclic group (e.g., indolinyl,    dihydrobenzoxadinyl (2,3-dihydro-1,4-benzoxadinyl),    tetrahydroquinolyl (e.g., 1,2,3,4-tetrahydroquinolyl)) optionally    substituted by 1 to 3 oxo groups,

-   (8) a 8- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) aromatic heterocyclic group (e.g., pyrrolopyridyl    (pyrrolo[2,3-b]pyridyl), pyrazolopyridyl    (1H-pyrazolo[3,4-b]pyridyl)),

-   (9) a C₁₋₁₂ alkoxy-carbonyl group (e.g., ethoxycarbonyl),

-   (10) a 5- to 14-membered spiro heterocyclic group (e.g.,    2-oxa-6-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl),

-   (11) a 3- to 8-membered monocyclic non-aromatic heterocyclyloxy    group (e.g., oxetanyloxy), or

-   (12) an amino group optionally mono- or di-substituted by    substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., ethyl, isobutyl) optionally        substituted by 1 to 3 hydroxy groups, and    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridazinyl),        or a salt thereof.        [Compound A-4]

A compound wherein

Ring A is a 6-membered aromatic ring (preferably a benzene ring)optionally further substituted by 1 to 3 substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (2) a cyano group;        R¹ is

-   (1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   Q is a carbon atom, a silicon atom or a germanium atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (b) a hydroxy group, or    -   (c) a cyano group,

-   (2) a neopentyl group, or

-   (3) a trimethylsilylmethyl group;    R² is

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is    -   (A) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (a) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy)            optionally substituted by 1 to 3 substituents selected from            -   (i) a halogen atom (e.g., a fluorine atom), and            -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy), and        -   (b) a hydroxy group, or    -   (B) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy)        optionally substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g.,        methoxy), and    -   the benzene ring in the formula optionally has, besides R⁵,        additional 1 to 3 substituents selected from        -   (A) a C₁₋₆ alkyl group (e.g., methyl), and        -   (B) a C₁₋₆ alkoxy group (e.g., methoxy),

-   (2) a bicyclic fused heterocyclic group (e.g., dihydrobenzofuryl    (2,3-dihydrobenzofuryl), indazolyl (1H-indazolyl, 2H-indazolyl),    indolyl, indolinyl) optionally substituted by 1 to 3 C₁₋₆ alkyl    groups (e.g., methyl), or

-   (3) a group represented by the formula -L-Z¹:    -   wherein    -   L is a bond; and    -   Z¹ is    -   (A) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally        substituted by 1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom), and        -   (b) a hydroxy group, or    -   (B) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, piperidyl,        1,1-dioxidotetrahydrothiopyranyl) optionally substituted by C₁₋₆        alkyl group(s) (e.g., ethyl) optionally substituted by 1 to 3        halogen atoms (e.g., a fluorine atom);        R³ is

-   (1) a hydrogen atom, or

-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted    by 1 to 3 cyano groups; and    R⁴ is

-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,    butyl, isobutyl, tert-butyl) optionally substituted by 1 to 7    substituents selected from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyrimidinyl (1,6-dihydropyrimidinyl),        dihydropyridyl (1,2-dihydropyridyl, 1,4-dihydropyridyl),        tetrahydropyrimidinyl (1,2,3,4-tetrahydropyrimidinyl),        dihydropyridazinyl (1,4-dihydropyridazinyl,        2,3-dihydropyridazinyl), imidazolidinyl, tetrahydropyranyl,        morpholinyl, piperidyl, dihydrooxadiazolyl        (4,5-dihydro-1,2,4-oxadiazolyl), pyrrolidinyl, tetrahydrofuryl,        piperazinyl, thiazolidinyl, oxazolidinyl, azetidinyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) an oxo group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),        -   (iii) a hydroxy group, and        -   (iv) a cyano group,    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl), isoxazolyl, pyrazolyl,        pyridyl, imidazolyl (1H-imidazolyl), thienyl, tetrazolyl        (1H-tetrazolyl)) optionally substituted by 1 to 3 substituents        selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally            substituted by 1 to 3 substituents selected from a halogen            atom (e.g., a fluorine atom) and a C₆₋₁₄ aryl group (e.g.,            phenyl),        -   (ii) a hydroxy group, and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),    -   (c) a 8- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) aromatic heterocyclic group (e.g., indazolyl        (1H-indazolyl), benzisoxazolyl (benzo[d]isoxazolyl),        benzimidazolyl (1H-benzimidazolyl)),    -   (d) a 9- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) non-aromatic heterocyclic group (e.g.,        dihydrobenzoxazolyl(2,3-dihydrobenzoxazolyl)) optionally        substituted by 1 to 3 oxo groups,    -   (e) a halogen atom (e.g., a fluorine atom),    -   (f) a hydroxy group,    -   (g) a cyano group,    -   (h) a carboxy group,    -   (i) a carbamoyl group,    -   (j) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (k) a C₃₋₁₀ cycloalkyl group (e.g., cyclopentyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a cyano group,    -   (l) an amino group optionally mono- or di-substituted by        substituent(s) selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl),        -   (ii) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl), and        -   (iii) a C₁₋₆ alkoxy-carbonyl group (e.g.,            tert-butoxycarbonyl),    -   (m) an imino group optionally substituted by a hydroxy group,        and    -   (n) a 5- or 6-membered monocyclic aromatic heterocyclyloxy group        (e.g., pyrazolyloxy) optionally substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl),

-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl,    tetrahydropyranyl, tetrahydrothiopyranyl,    1,1-dioxidotetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl,    imidazolidinyl, tetrahydrofuryl, 1,1-dioxidotetrahydrothienyl,    morpholinyl, dihydrooxazolyl (2,3-dihydrooxazolyl), dihydrothiazolyl    (2,3-dihydrothiazolyl), piperazinyl, dihydrooxadiazolyl    (4,5-dihydro-1,2,4-oxadiazolyl), pyrrolyl (2H-pyrrolyl)) optionally    substituted by 1 to 3 substituents selected from    -   (a) an oxo group,    -   (b) a hydroxy group,    -   (c) a cyano group,    -   (d) a halogen atom (e.g., a fluorine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),    -   (g) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl), and    -   (h) a C₁₋₄ alkylidene group (e.g., methylidene (═CH₂))        optionally substituted by 5- or 6-membered monocyclic aromatic        heterocyclic group(s) (e.g., pyrrolyl (1H-pyrrolyl)) optionally        substituted by 1 to 3 substituents selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl), and        -   (ii) a halogenated boryl group (e.g., difluoroboryl),

-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl, furyl, pyridyl, imidazolyl (1H-imidazolyl), pyrazolyl,    thienyl, triazolyl (1,2,4-triazolyl), oxazolyl, thiazolyl,    oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted by 1 to 3    substituents selected from    -   (a) a hydroxy group,    -   (b) a cyano group,    -   (c) a carboxy group,    -   (d) a halogen atom (e.g., a fluorine atom, a bromine atom),    -   (e) a C₁₋₄ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (h) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl-carbonyl group(s) (e.g., acetyl),

-   (4) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl) optionally substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a hydroxy group,    -   (c) an oxo group,    -   (d) a cyano group,    -   (e) a carboxy group, and    -   (f) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,

-   (5) a C₂₋₆ alkenyl group (e.g., allyl) optionally substituted by 1    to 3 substituents selected from    -   (a) a carbamoyl group, and    -   (b) a hydroxy group,

-   (6) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to    3 hydroxy groups,

-   (7) a 9- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) non-aromatic heterocyclic group (e.g., indolinyl,    dihydrobenzoxadinyl (2,3-dihydro-1,4-benzoxadinyl),    tetrahydroquinolyl (e.g., 1,2,3,4-tetrahydroquinolyl)) so optionally    substituted by 1 to 3 oxo groups,

-   (8) a 8- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) aromatic heterocyclic group (e.g., pyrrolopyridyl    (pyrrolo[2,3-b]pyridyl), pyrazolopyridyl    (1H-pyrazolo[3,4-b]pyridyl)),

-   (9) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl),

-   (10) a 5- to 14-membered spiro heterocyclic group (e.g.,    2-oxa-6-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl),

-   (11) a 3- to 8-membered monocyclic non-aromatic heterocyclyloxy    group (e.g., oxetanyloxy), or

-   (12) an amino group optionally mono- or di-substituted by    substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., ethyl, isobutyl) optionally        substituted by 1 to 3 hydroxy groups, and    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridazinyl); or        when R³ is a substituent, R³ and R⁴ in combination form,        together with the nitrogen atom adjacent to R³ and the carbon        atom adjacent to R⁴, a 3- to 14-membered non-aromatic        heterocycle (containing a spiro ring) (e.g., pyrrolidine,        2,7-diazaspiro[4.4]nonane) substituted by one oxo group and        optionally further substituted by 1 to 3 oxo groups, or a salt        thereof.        [Compound A-5]

A compound wherein

Ring A is a 6-membered aromatic ring (preferably a benzene ring)optionally further substituted by 1 to 3 substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (2) a cyano group;        R¹ is

-   (1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   Q is a carbon atom, a silicon atom or a germanium atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),    -   (b) a hydroxy group,    -   (c) a C₆₋₁₄ aryl group (e.g., phenyl),    -   (d) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    -   (e) a cyano group,    -   (f) a carbamoyl group optionally mono- or di-substituted by        C₃₋₁₀ cycloalkyl group(s) (e.g., cyclopropyl), or    -   (g) a 3- to 8-membered monocyclic non-aromatic        heterocyclylcarbonyl group (e.g., pyrrolidinylcarbonyl), or    -   R^(1a) and R^(1b) in combination form, together with the        adjacent Q, a C₃₋₁₀ cycloalkane ring (e.g., cyclopentane),

-   (2) a neopentyl group, or

-   (3) a trimethylsilylmethyl group;    R² is

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is    -   (A) a C₁₋₆ alkyl group (e.g., methyl, ethyl, isopropyl)        optionally substituted by 1 to 3 substituents selected from        -   (a) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy)            optionally substituted by 1 to 3 substituents selected from            -   (i) a halogen atom (e.g., a fluorine atom), and            -   (ii) a C₁₋₆ alkoxy group (e.g., methoxy), and        -   (b) a hydroxy group, or    -   (B) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, propoxy)        optionally substituted by 1 to 3 C₁₋₆ alkoxy groups (e.g.,        methoxy), and    -   the benzene ring in the formula optionally has, besides R⁵,        additional 1 to 3 substituents selected from        -   (A) a C₁₋₆ alkyl group (e.g., methyl), and        -   (B) a C₁₋₆ alkoxy group (e.g., methoxy),

-   (2) a bicyclic fused heterocyclic group (e.g., dihydrobenzofuryl    (2,3-dihydrobenzofuryl), indazolyl (1H-indazolyl, 2H-indazolyl),    indolyl, indolinyl) optionally substituted by 1 to 3 C₁₋₆ alkyl    groups (e.g., methyl), or

-   (3) a group represented by the formula -L-Z¹:    -   wherein    -   L is a bond; and    -   Z¹ is    -   (A) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally        substituted by 1 to 3 substituents selected from        -   (a) a halogen atom (e.g., a fluorine atom), and        -   (b) a hydroxy group, or    -   (B) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl, piperidyl,        1,1-dioxidotetrahydrothiopyranyl) optionally substituted by C₁₋₆        alkyl group(s) (e.g., ethyl) optionally substituted by 1 to 3        halogen atoms (e.g., a fluorine atom);        R³ is

-   (1) a hydrogen atom, or

-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted    by 1 to 3 cyano groups; and    R⁴ is

-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,    butyl, isobutyl, tert-butyl) optionally substituted by 1 to 7    substituents selected from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyrimidinyl (1,6-dihydropyrimidinyl),        dihydropyridyl (1,2-dihydropyridyl, 1,4-dihydropyridyl),        tetrahydropyrimidinyl (1,2,3,4-tetrahydropyrimidinyl),        dihydropyridazinyl (1,4-dihydropyridazinyl,        2,3-dihydropyridazinyl), imidazolidinyl, tetrahydropyranyl,        morpholinyl, piperidyl, dihydrooxadiazolyl        (4,5-dihydro-1,2,4-oxadiazolyl), pyrrolidinyl, tetrahydrofuryl,        piperazinyl, thiazolidinyl, oxazolidinyl, azetidinyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) an oxo group,        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),        -   (iii) a hydroxy group, and        -   (iv) a cyano group,    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl), isoxazolyl, pyrazolyl,        pyridyl, imidazolyl (1H-imidazolyl), thienyl, tetrazolyl        (1H-tetrazolyl)) optionally substituted by 1 to 3 substituents        selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally            substituted by 1 to 3 substituents selected from a halogen            atom (e.g., a fluorine atom) and a C₆₋₁₄ aryl group (e.g.,            phenyl),        -   (ii) a hydroxy group, and        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy) optionally            substituted by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl),    -   (c) a 8- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) aromatic heterocyclic group (e.g., indazolyl        (1H-indazolyl), benzisoxazolyl (benzo[d]isoxazolyl),        benzimidazolyl (1H-benzimidazolyl)),    -   (d) a 9- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) non-aromatic heterocyclic group (e.g.,        dihydrobenzoxazolyl(2,3-dihydrobenzoxazolyl)) optionally        substituted by 1 to 3 oxo groups,    -   (e) a halogen atom (e.g., a fluorine atom),    -   (f) a hydroxy group,    -   (g) a cyano group,    -   (h) a carboxy group,    -   (i) a carbamoyl group,    -   (j) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (k) a C₃₋₁₀ cycloalkyl group (e.g., cyclopentyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group, and        -   (ii) a cyano group,    -   (l) an amino group optionally mono- or di-substituted by        substituent(s) selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl),        -   (ii) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl), and        -   (iii) a C₁₋₆ alkoxy-carbonyl group (e.g.,            tert-butoxycarbonyl),    -   (m) an imino group optionally substituted by a hydroxy group,        and    -   (n) a 5- or 6-membered monocyclic aromatic heterocyclyloxy group        (e.g., pyrazolyloxy) optionally substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl),

-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl,    tetrahydropyranyl, tetrahydrothiopyranyl,    1,1-dioxidotetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl,    imidazolidinyl, tetrahydrofuryl, 1,1-dioxidotetrahydrothienyl,    morpholinyl, dihydrooxazolyl (2,3-dihydrooxazolyl), dihydrothiazolyl    (2,3-dihydrothiazolyl), piperazinyl, dihydrooxadiazolyl    (4,5-dihydro-1,2,4-oxadiazolyl)) optionally substituted by 1 to 3    substituents selected from    -   (a) an oxo group,    -   (b) a hydroxy group,    -   (c) a cyano group,    -   (d) a halogen atom (e.g., a fluorine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 C₆₋₁₄ aryl groups (e.g., phenyl), and    -   (g) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl),

-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl, furyl, pyridyl, imidazolyl (1H-imidazolyl), pyrazolyl,    thienyl, triazolyl (1,2,4-triazolyl), oxazolyl, thiazolyl,    oxadiazolyl (1,3,4-oxadiazolyl)) optionally substituted by 1 to 3    substituents selected from    -   (a) a hydroxy group,    -   (b) a cyano group,    -   (c) a carboxy group,    -   (d) a halogen atom (e.g., a fluorine atom, a bromine atom),    -   (e) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,    -   (f) a C₁₋₆ alkoxy group (e.g., methoxy),    -   (g) a C₁₋₆ alkoxy-carbonyl group (e.g., methoxycarbonyl), and    -   (h) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl-carbonyl group(s) (e.g., acetyl),

-   (4) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl) optionally substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a hydroxy group,    -   (c) an oxo group,    -   (d) a cyano group,    -   (e) a carboxy group, and    -   (f) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 hydroxy groups,

-   (5) a C₂₋₆ alkenyl group (e.g., allyl) optionally substituted by 1    to 3 substituents selected from    -   (a) a carbamoyl group, and    -   (b) a hydroxy group,

-   (6) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by 1 to    3 hydroxy groups,

-   (7) a 9- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) non-aromatic heterocyclic group (e.g., indolinyl,    dihydrobenzoxadinyl (2,3-dihydro-1,4-benzoxadinyl),    tetrahydroquinolyl (e.g., 1,2,3,4-tetrahydroquinolyl)) optionally    substituted by 1 to 3 oxo groups,

-   (8) a 8- to 14-membered fused polycyclic (preferably bi- or    tri-cyclic) aromatic heterocyclic group (e.g., pyrrolopyridyl    (pyrrolo[2,3-b]pyridyl), pyrazolopyridyl    (1H-pyrazolo[3,4-b]pyridyl)),

-   (9) a C₁₋₆ alkoxy-carbonyl group (e.g., ethoxycarbonyl),

-   (10) a 5- to 14-membered spiro heterocyclic group (e.g.,    2-oxa-6-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl),

-   (11) a 3- to 8-membered monocyclic non-aromatic heterocyclyloxy    group (e.g., oxetanyloxy),

-   (12) a C₁₋₄ alkoxy group (e.g., methoxy, ethoxy) optionally    substituted by 1 to 3 substituents selected from    -   (a) a C₆₋₁₄ aryl group (e.g., phenyl), and    -   (b) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., oxetanyl), or

-   (13) an amino group optionally mono- or di-substituted by    substituent(s) selected from    -   (a) a C₁₋₆ alkyl group (e.g., ethyl, isobutyl) optionally        substituted by 1 to 3 hydroxy groups, and    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyridazinyl), or        when R³ is a substituent, R³ and R⁴ in combination form,        together with the nitrogen atom adjacent to R³ and the carbon        atom adjacent to R⁴, a 3- to 14-membered non-aromatic        heterocycle (e.g., pyrrolidine, 2,7-diazaspiro[4.4]nonane)        substituted by one oxo group and optionally further substituted        by 1 to 3 oxo groups,        or a salt thereof.        [Compound B-1]

A compound wherein

Ring A is a benzene ring optionally further substituted by 1 to 3substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (2) a cyano group;        R¹ is

-   (1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently a C₁₋₆ alkyl        group (e.g., methyl), or

-   (2) a neopentyl group;    R¹ is

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is    -   (A) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), or    -   (B) a C₁₋₆ alkoxy group (e.g., methoxy),

-   (2) a bicyclic fused heterocyclic group (e.g., dihydrobenzofuryl    (2,3-dihydrobenzofuryl), indazolyl (1H-indazolyl)) optionally    substituted by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl), or

-   (3) a group represented by the formula -L-Z¹:    -   wherein    -   L is a bond; and    -   Z¹ is    -   (A) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or    -   (B) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl);        R³ is

-   (1) a hydrogen atom, or

-   (2) a C₁₋₆ alkyl group (e.g., methyl); and    R⁴ is

-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isobutyl)    optionally substituted by 1 to 7 substituents selected from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., dihydropyrimidinyl (1,6-dihydropyrimidinyl),        dihydropyridyl (1,2-dihydropyridyl, 1,4-dihydropyridyl),        dihydropyridazinyl (1,4-dihydropyridazinyl,        2,3-dihydropyridazinyl), imidazolidinyl, tetrahydropyranyl,        morpholinyl, piperidyl, tetrahydropyrimidinyl        (1,2,3,4-tetrahydropyrimidinyl)) optionally substituted by 1 to        3 substituents selected from        -   (i) an oxo group, and        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),    -   (b) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., oxadiazolyl (1,3,4-oxadiazolyl), isoxazolyl, pyrazolyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a C₁₋₆ alkyl group (e.g., methyl), and        -   (ii) a hydroxy group,    -   (c) a 8- to 14-membered fused polycyclic (preferably bi- or        tri-cyclic) aromatic heterocyclic group (e.g., indazolyl        (1H-indazolyl), benzimidazolyl (1H-benzimidazolyl)),    -   (d) a halogen atom (e.g., a fluorine atom),    -   (e) a hydroxy group,    -   (f) a cyano group,    -   (g) a carboxy group,    -   (h) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl), and    -   (i) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl-carbonyl group(s) (e.g., acetyl),

-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl,    tetrahydropyranyl) optionally substituted by 1 to 3 substituents    selected from    -   (a) an oxo group,    -   (b) a hydroxy group,    -   (c) a halogen atom (e.g., a fluorine atom), and    -   (d) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl),

-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,

-   (4) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl)    optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine    atom), or

-   (5) an amino group optionally mono- or di-substituted by C₁₋₆ alkyl    group(s) (e.g., ethyl),    or a salt thereof.    [Compound B-2]

A compound wherein

Ring A is a benzene ring optionally further substituted by 1 to 3substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (2) a cyano group;        R¹ is    -   (1) a group represented by the formula:        -Q(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently a C₁₋₆ alkyl        group (e.g., methyl), or

-   (2) a neopentyl group;    R² is

-   (1) a group represented by the formula:

-   -   wherein    -   R³ is    -   (A) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), or    -   (B) a C₁₋₆ alkoxy group (e.g., methoxy),

-   (2) a bicyclic fused heterocyclic group (e.g., dihydrobenzofuryl    (2,3-dihydrobenzofuryl), indazolyl (1H-indazolyl)) optionally    substituted by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl), or

-   (3) a group represented by the formula -L-Z¹:    -   wherein    -   L is a bond; and    -   Z¹ is    -   (A) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or    -   (B) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl);        R³ is

-   (1) a hydrogen atom, or

-   (2) a C₁₋₆ alkyl group (e.g., methyl); and    R⁴ is

-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isobutyl)    optionally substituted by 1 to 7 substituents selected from    -   (a) a 3- to 8-membered monocyclic oxygen-containing non-aromatic        heterocyclic group (e.g., tetrahydropyranyl),    -   (b) a halogen atom (e.g., a fluorine atom),    -   (c) a cyano group,    -   (d) a carboxy group, and    -   (e) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),

-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl,    tetrahydropyranyl) optionally substituted by 1 to 3 substituents    selected from    -   (a) an oxo group,    -   (b) a hydroxy group,    -   (c) a halogen atom (e.g., a fluorine atom), and    -   (d) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl),

-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,

-   (4) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl)    optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine    atom), or

-   (5) an amino group optionally mono- or di-substituted by C₁₋₆ alkyl    group(s) (e.g., ethyl),    or a salt thereof.    [Compound B-3]

A compound wherein

Ring A is a benzene ring optionally further substituted by 1 to 3substituents selected from

-   -   (1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and    -   (2) a cyano group;        R¹ is

-   (1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))    -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently a C₁₋₆ alkyl        group (e.g., methyl), or

-   (2) a neopentyl group;    R² is

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is    -   (A) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 C₁₋₆ alkoxy groups (e.g., methoxy), or    -   (B) a C₁₋₆ alkoxy group (e.g., methoxy),

-   (2) a bicyclic fused heterocyclic group (e.g., dihydrobenzofuryl    (2,3-dihydrobenzofuryl), indazolyl (1H-indazolyl)) optionally    substituted by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl), or

-   (3) a group represented by the formula -L-Z¹:    -   wherein    -   L is a bond; and    -   Z¹ is    -   (A) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or    -   (B) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl);        R³ is

-   (1) a hydrogen atom, or

-   (2) a C₁₋₆ alkyl group (e.g., methyl); and    R⁴ is

-   (1) a C₁₋₁₂ alkyl group (e.g., methyl, ethyl, propyl, isobutyl)    optionally substituted by 1 to 7 substituents selected from    -   (a) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group not containing a nitrogen atom as a ring constituting atom        (e.g., tetrahydropyranyl) optionally substituted by 1 to 3        substituents selected from        -   (i) an oxo group, and        -   (ii) a C₁₋₆ alkyl group (e.g., methyl),    -   (b) a halogen atom (e.g., a fluorine atom),    -   (c) a cyano group,    -   (d) a carboxy group, and    -   (e) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),

-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl, oxazolidinyl, azetidinyl, piperidyl,    tetrahydropyranyl) optionally substituted by 1 to 3 substituents    selected from    -   (a) an oxo group,    -   (b) a hydroxy group,    -   (c) a halogen atom (e.g., a fluorine atom), and    -   (d) a C₁₋₆ alkyl-carbonyl group (e.g., acetyl),

-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,

-   (4) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl)    optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine    atom), or

-   (5) an amino group optionally mono- or di-substituted by C₁₋₆ alkyl    group(s) (e.g., ethyl),    or a salt thereof.    [Compound C-1]

A compound wherein

Ring A is a benzene ring optionally further substituted by 1 to 3halogen atoms (e.g., a fluorine atom);

R¹ is a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently a C₁₋₆ alkyl        group (e.g., methyl);        R² is

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is C₁₋₆ alkoxy group (e.g., methoxy),

-   (2) a bicyclic fused heterocyclic group (e.g., indazolyl    (1H-indazolyl)) optionally substituted by 1 to 3 C₁₋₆ alkyl groups    (e.g., methyl), or

-   (3) a group represented by the formula -L-Z¹:    -   wherein    -   L is a bond; and    -   Z¹ is a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom);        R³ is

-   (1) a hydrogen atom, or

-   (2) a C₁₋₆ alkyl group (e.g., methyl); and    R⁴ is

-   (1) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by 5-    or 6-membered monocyclic aromatic heterocyclic group(s) (e.g.,    isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,

-   (2) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl) optionally substituted by 1 to 3 oxo groups, or

-   (3) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,    or a salt thereof.    [Compound C-2]

A compound wherein

Ring A is a benzene ring optionally further substituted by 1 to 3halogen atoms (e.g., a fluorine atom);

R¹ is a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))

-   -   wherein    -   Q is a carbon atom or a silicon atom, and    -   R^(1a), R^(1b) and R^(1c) are each independently a C₁₋₆ alkyl        group (e.g., methyl);        R² is

-   (1) a group represented by the formula:

-   -   wherein    -   R⁵ is C₁₋₆ alkoxy group (e.g., methoxy),

-   (2) a bicyclic fused heterocyclic group (e.g., indazolyl    (1H-indazolyl)) optionally substituted by 1 to 3 C₁₋₆ alkyl groups    (e.g., methyl), or

-   (3) a group represented by the formula -L-Z¹:    -   wherein    -   L is a bond; and    -   Z¹ is a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom);        R³ is

-   (1) a hydrogen atom, or

-   (2) a C₁₋₆ alkyl group (e.g., methyl); and    R⁴ is

-   (1) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., pyrrolidinyl) optionally substituted by 1 to 3 oxo groups, or

-   (2) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    isoxazolyl) optionally substituted by 1 to 3 hydroxy groups,    or a salt thereof.    [Compound D-1]

-   (3S)—N-((1R)-2-((4-tert-butyl-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide    or a salt thereof.    [Compound D-2]

-   N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide    or a salt thereof.    [Compound D-3]

-   (2R)—N-(4-tert-butyl-3,5-difluorophenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)-2-(1-methyl-1H-indazol-5-yl)acetamide    or a salt thereof.

Specific Examples of the above-mentioned compound (I), compound (I′) andcompound (I″) include the compounds of Examples 1 to 126, 128 to 154,156 to 214, 216 to 253, 255 to 382, 384 to 402, 406, 407, 409 to 419 and421 to 427.

Examples of salts of compound (I), compound (I′) and compound (I″)include metal salts, ammonium salts, salts with organic base, salts withinorganic acid, salts with organic acid, salts with basic or acidicamino acids, and the like. Preferable examples of the metal salt includealkaline metal salts such as sodium salt, potassium salt and the like;alkaline earth metal salts such as calcium salt, magnesium salt, bariumsalt and the like; aluminum salts, and the like. Preferable examples ofthe salt with organic base include salts with trimethylamine,triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine,diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine,N,N′-dibenzylethylenediamine and the like. Preferable examples of thesalt with inorganic acid include salts with hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and thelike. Preferable examples of the salt with organic acid include saltswith formic acid, acetic acid, trifluoroacetic acid, phthalic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like. Preferable examples of the saltwith basic amino acid include salts with arginine, lysine, ornithine andthe like. Preferable examples of the salt with acidic amino acid includesalt with aspartic acid, glutamic acid and the like.

Among them, pharmaceutically acceptable salts are preferable. Forexample, if the compound has an acidic functional group therein,examples of the salt include inorganic salts such as alkaline metalsalts (e.g., sodium salt, potassium salt and the like), alkaline earthmetal salts (e.g., calcium salt, magnesium salt, barium salt and thelike) and the like; ammonium salt, and the like. If the compound has abasic functional group therein, examples of the salt thereof includesalts with inorganic acids such as hydrochloric acid, hydrobromic acid,nitric acid, sulfuric acid, phosphoric acid and the like, and salts withorganic acids such as acetic acid, phthalic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid,methanesulfonic acid, p-toluenesulfonic acid and the like.

Next, The production methods of compound (I), compound (I′) and compound(I″) of the present invention are explained.

The intermediates produced in the following production methods may beisolated and purified according to methods such as columnchromatography, recrystallization, distillation and the like, or may bedirectly used without isolation for the next step.

Compound (I), compound (I′) and compound (I″) of the present inventioncan be produced according to the following Method A. Compound (I),compound (I′) and compound (I″) wherein R³ and R⁴ in combination form,together with the nitrogen atom adjacent to R³ and the carbon atomadjacent to R⁴, an optionally substituted ring can be produced accordingto Step 3.

wherein each symbol is as defined above.(Step 1)

This step is a step of subjecting compound (II) or a salt thereof to anacylation reaction to convert compound (II) or a salt thereof intocompound (I), compound (I′) or compound (I″).

In the acylation reaction, compound (I), compound (I′) or compound (I″)can be produced by reacting compound (II) or a salt thereof with acompound represented by the formula:

wherein symbol is as defined above (hereinafter to be referred to ascompound (IV)) or a salt thereof.

Compound (IV) or a salt thereof may be a commercially available product,or can also be produced according to a method known per se or a methodanalogous thereto.

The acylation reaction can be carried out according to a method knownper se, for example, the method described in Jikken Kagaku Kouza, 4thEdition, 1991, vol. 22, organic synthesis IV (the Chemical Society ofJapan ed.) and the like, or a method analogous thereto. Examples of themethod include a method using a condensing agent, a method via areactive derivative, and the like.

Examples of the condensing agent to be used for the “method using acondensing agent” include(dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaneiminiumhexafluorophosphorate (HATU),1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholino)]carbeniumhexafluorophosphorate (COMU),2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P),dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),N-ethyl-N′-3-dimethylaminopropylcarbodiimide and a hydrochloride thereof(WSC, WSC.HCl, EDCI), benzotriazol-1-yl-tris(dimethylamino)phosphoniumhexafluorophosphorate (BOP), diphenylphosphorylazide(DPPA) and the like.They can be used alone or in combination with an additive (e.g.,N-hydroxysuccinimide, 1-hydroxybenzotriazole or3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine, etc.). The amount ofthe condensing agent to be used is about 1 to 10 mol equivalent,preferably about 1 to 2 mol equivalent, per 1 mol of compound (II). Theamount of the additive to be used is about 1 to 10 mol equivalent,preferably about 1 to 2 mol equivalent, per 1 mol of compound (II).

The above-mentioned reaction is generally carried out in a solvent thatdoes not adversely influence the reaction, and a base may be added forthe progress of the reaction. Examples of the solvent includehydrocarbons (benzene, toluene etc.), ethers (diethyl ether, dioxane,tetrahydrofuran etc.), esters (ethyl acetate etc.), halogenatedhydrocarbons (chloroform, dichloromethane etc.), amides(N,N-dimethylformamide etc.), aromatic amines (pyridine etc.), water andthe like, and they may be mixed as appropriate. Examples of the baseinclude alkali metal hydroxides (sodium hydroxide, potassium hydroxideetc.), hydrogencarbonates (sodium hydrogencarbonate, potassiumhydrogencarbonate etc.), carbonates (sodium carbonate, potassiumcarbonate etc.), acetates (sodium acetate etc.), tertiary amines(trimethylamine, triethylamine, N-methylmorpholine,diisopropylethylamine etc.), aromatic amines (pyridine, picoline,N,N-dimethylaniline, 4-dimethylaminopyridine etc.) and the like. Theamount of the base to be used is generally about 1 to 100 molequivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (II). The reaction temperature is generally about −80 to 150°C., preferably about 0 to 50° C., and the reaction time is generallyabout 0.5 to 48 hr, preferably 0.5 to 16 hr.

Examples of the reactive derivative to be used for the “method via areactive derivative” include a compound represented by the formula:

wherein LG is a leaving group, and the other symbols are as definedabove (hereinafter to be referred to as compound (IVa)) or a saltthereof (e.g., acid halides, anhydrides, mixed anhydrides, activatedesters etc.) and the like.

Examples of the leaving group represented by LG include halogen atoms (achlorine atom, a bromine atom, an iodine atom etc.), substitutedsulfonyloxy groups (C₁₋₆ alkylsulfonyloxy groups such asmethanesulfonyloxy, ethanesulfonyloxy and the like; C₆₋₁₄arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxyand the like; C₇₋₁₆ aralkylsulfonyloxy groups such as benzylsulfonyloxygroup and the like, etc.), acyloxy groups (acetoxy, benzoyloxy etc.),oxy groups substituted by a heterocyclic group or an aryl group(2,5-dioxo-1-pyrrolidinyl, benzotriazolyl, quinolyl, 4-nitrophenyletc.), heterocyclic groups (imidazolyl etc.) and the like.

The conversion of compound (IV) into the reactive derivative (compound(IVa)) can be carried out according to a method known per se. Forexample, the conversion into the acid halide can be carried out byemploying a method using an acid halide (e.g., thionyl chloride, oxalylchloride, etc.), a method using a halide of phosphorus and phosphoricacid (e.g., phosphorus trichloride, phosphorus pentachloride, etc.), andthe like. The method using a reactive derivative is generally carriedout in a solvent that does not adversely influence the reaction, whichvaries depending on the kind of compound (IVa), and a base may be addedfor the progress of the reaction. The kind and amount of the solvent andbase to be used for the reaction, the reaction temperature and thereaction time are the same as in the above-mentioned “method using acondensing agent”.

(Step 2)

This step is a step of subjecting compound (II) or a salt thereof to anureation reaction to convert compound (II) or a salt thereof intocompound (I), compound (I′) or compound (I′).

In the ureation reaction, compound (I), compound (I′) or compound (I″)can be produced by reacting compound (II) or a salt thereof with thereactive intermediate (obtained by reacting a compound represented bythe formula:R⁴—H  (V)wherein symbol is as defined above (hereinafter to be referred to ascompound (V)) or a salt thereof with a carbonylating agent), or byreacting the reactive intermediate (obtained by reacting compound (II)or a salt thereof with a carbonylating agent) with compound (V) or asalt thereof.

Compound (V) may be a commercially available product, or can also beproduced according to a method known per se or a method analogousthereto.

Examples of the carbonylating agent to be used in this step includetriphosgene, 4-nitrophenyl chloroformate or carbonyldiimidazole and thelike. The amount of the carbonylating agent to be used is about 1 to 10mol equivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (II).

The above-mentioned reaction is generally carried out in a solvent thatdoes not adversely influence the reaction, and a base may be added forthe progress of the reaction. Examples of the solvent includehydrocarbons (benzene, toluene etc.), ethers (diethyl ether, dioxane,tetrahydrofuran etc.), esters (ethyl acetate etc.), halogenatedhydrocarbons (chloroform, dichloromethane etc.), amides(N,N-dimethylformamide etc.) and the like, and they may be mixed asappropriate. Examples of the base include alkali metal hydroxides(sodium hydroxide, potassium hydroxide etc.), hydrogencarbonates (sodiumhydrogencarbonate, potassium hydrogencarbonate etc.), carbonates (sodiumcarbonate, potassium carbonate etc.), acetates (sodium acetate etc.),tertiary amines (trimethylamine, triethylamine, N-methylmorpholineetc.), aromatic amines (pyridine, picoline, N,N-dimethylaniline etc.)and the like. The amount of the base to be used is generally about 1 to100 mol equivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (II). The reaction temperature is generally about −80 to 150°C., preferably about 0 to 50° C., and the reaction time is generallyabout 0.5 to 100 hr, preferably about 0.5 to 60 hr.

The reactive intermediate obtained by the reaction of compound (V) or asalt thereof with a carbonylating agent may be reacted with compound(II) or a salt thereof after isolation.

The reactive intermediate obtained by the reaction of compound (II) or asalt thereof with a carbonylating agent may be reacted with compound (V)or a salt thereof after isolation.

(Step 3)

This step is a step of reacting compound (III) or a salt thereof with acompound represented by the formula:

wherein each symbol is as defined above (hereinafter to be referred toas compound (VI)) or a salt thereof in the presence of a condensingagent to produce compound (I), compound (I′) or compound (I″).

Compound (VI) or a salt thereof may be a commercially available product,or can also be produced according to a method known per se, a methodanalogous thereto, or the below-mentioned method.

This step can be performed in the same manner as in the method describedin Step 1 of Method A.

The raw materials used in Method A can be produced according to thefollowing Methods B-I.

wherein R¹⁶ is an allyl group or a benzyl group, and the other symbolsare as defined above.(Step 1)

This step is a step of reacting compound (VII) or a salt thereof orcompound (VIII) or a salt thereof with glyoxylic acid and compound (IX)or a salt thereof to produce compound (X) or a salt thereof.

The compounds used for this reaction may be a commercially availableproduct, or can also be produced according to a method known per se or amethod analogous thereto.

The amount of the glyoxylic acid to be used is generally about 1 to 10mol equivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (VII) or compound (VIII).

The amount of compound (IX) to be used is generally about 1 to 10 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (VII) or compound (VIII).

The above-mentioned reaction is generally carried out in a solvent thatdoes not adversely influence the reaction. Examples of the solventinclude nitriles (acetonitrile etc.), hydrocarbons (benzene, tolueneetc.), ethers (diethyl ether, dioxane, tetrahydrofuran etc.), esters(ethyl acetate etc.), halogenated hydrocarbons (chloroform,dichloromethane etc.), amides (N,N-dimethylformamide etc.) and the like,and they may be mixed as appropriate. The reaction temperature isgenerally about −80 to 150° C., preferably about 0 to 10° C., and thereaction time is generally about 0.5 to 100 hr, preferably about 0.5 to60 hr.

(Step 2)

This step is a step of reacting compound (X) or a salt thereof withcompound (VI) or a salt thereof in the presence of a condensing agent toproduce compound (XI) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method A.

(Step 3)

This step is a step of subjecting compound (XI) or a salt thereof to adeallylation reaction or a debenzylation reaction to produce compound(II) or a salt thereof.

The deallylation reaction is carried out by reacting compound (XI) or asalt thereof with thiosalicylic acid in the presence of Pd₂(dba)₃ and1,4-bis(diphenylphosphino)butane, in a solvent that does not adverselyinfluence the reaction, or by reacting compound (XI) or a salt thereofwith 1,3-dimethylbarbituric acid in the presence of Pd(PPh₃)₄, in asolvent that does not adversely influence the reaction.

The amount of the Pd₂(dba)₃ to be used is generally about 0.01 to 1 molequivalent, preferably about 0.05 to 0.2 mol equivalent, per 1 mol ofcompound (XI).

The amount of the 1,4-bis(diphenylphosphino)butane to be used is about 1to 2 mol equivalent per 1 mol of Pd₂(dba)₃.

The amount of the Pd(PPh₃)₄ to be used is generally about 0.01 to 1 molequivalent, preferably about 0.05 to 0.2 mol equivalent, per 1 mol ofcompound (XI).

The amount of the thiosalicylic acid or 1,3-dimethylbarbituric acid tobe used is generally about 1 to 5 mol equivalent, preferably about 1 to1.5 mol equivalent, per 1 mol of compound (XI).

Examples of the solvent that does not adversely influence the reactioninclude ethers (diethyl ether, dioxane, tetrahydrofuran etc.), nitriles(acetonitrile etc.), hydrocarbons (benzene, toluene etc.), esters (ethylacetate etc.), halogenated hydrocarbons (chloroform, dichloromethaneetc.), amides (N,N-dimethylformamide etc.) and the like, and they may bemixed as appropriate. The reaction temperature is generally about 0 to150° C., preferably about 10 to 30° C., and the reaction time isgenerally about 0.5 to 100 hr, preferably about 0.5 to 60 hr.

The debenzylation reaction can be carried out in the presence of apalladium catalyst (e.g., palladium on carbon, palladium hydroxide,palladium oxide), in a solvent that does not adversely influence thereaction, under hydrogen atmosphere.

The amount of the palladium catalyst to be used is generally about 0.01to 1 mol equivalent, preferably about 0.05 to 0.2 mol equivalent, per 1mol of compound (XI).

Examples of the solvent that does not adversely influence the reactioninclude alcohols (methanol, ethanol, propanol, 2-propanol etc.), ethers(diethyl ether, dioxane, tetrahydrofuran etc.), nitriles (acetonitrileetc.), hydrocarbons (benzene, toluene etc.), esters (ethyl acetate etc.)and the like, and they may be mixed as appropriate. The hydrogenpressure for the reaction is generally about 1 to 50 atm, preferablyabout 1 to 10 atm. The reaction temperature is generally about 0 to 150°C., preferably about 10 to 30° C., and the reaction time is generallyabout 0.5 to 100 hr, preferably about 0.5 to 60 hr.

wherein R¹¹ is a hydrocarbon group optionally having substituent(s), andthe other symbols are as defined above.(Step 1) Hydrolysis

This step is a step of subjecting compound (X) or a salt thereof toesterification to produce compound (XIII) or a salt thereof.

This reaction is a step of subjecting compound (X) or a salt thereof toa dehydration reaction with a compound represented by the formula:R¹¹—OH  (XII)wherein symbol is as defined above (hereinafter to be referred to ascompound (XII)) or a salt thereof in the presence of a acid catalyst toproduce compound (XIII) or a salt thereof, or a step of subjectingcompound (X) or a salt thereof to an alkylation reaction with a compoundrepresented by the formula:R¹¹-LG  (XIIa)wherein each symbol is as defined above (hereinafter to be referred toas compound (XIIa)) or a salt thereof in the presence of a base toproduce compound (XIII) or a salt thereof.

Compound (XII) and compound (XIIa) may be a commercially availableproduct, or can also be produced according to a method known per se or amethod analogous thereto.

Examples of the acid catalyst used for the reaction of compound (X) or asalt thereof with compound (XII) include mineral acids (hydrochloricacid, sulfuric acid etc.), organic sulfonic acids (methanesulfonic acid,p-toluenesulfonic acid etc.), Lewis acids (boron fluoride etherateetc.), thionyl chloride and the like. While the amount of the acidcatalyst to be used varies depending on the kind of the solvent and theother reaction condition, it is generally about 0.0001 to 10 molequivalent, preferably about 0.01 to 0.1 mol equivalent, per 1 mol ofcompound (X).

The amount of compound (XII) to be used is generally about 1 to 1000 molequivalent, preferably about 10 to 100 mol equivalent, per 1 mol ofcompound (X).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xyleneetc.), aliphatic hydrocarbons (hexane, heptane etc.), halogenatedhydrocarbons (dichloromethane, chloroform etc.), ethers (diethyl ether,diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,dimethoxyethane etc.), nitriles (acetonitrile etc.), esters (ethylacetate etc.) and the like. Compound (XII) may be used as a solvent.

The reaction temperature is, for example, within about 0 to 200° C.,preferably about 25 to 100° C. While the reaction time varies dependingon the kind of compound (X) or a salt thereof, the reaction temperatureand the like, it is, for example, about 0.5 to 100 hr, preferably about0.5 to 24 hr.

Examples of the base used for the reaction of compound (X) or a saltthereof with compound (XIIa) include inorganic bases (alkali metalhydrides such as sodium hydride, lithium hydride and the like, alkalimetal hydroxides such as lithium hydroxide, sodium hydroxide, potassiumhydroxide and the like, alkali metal hydrogencarbonates such as sodiumhydrogencarbonate, potassium hydrogencarbonate and the like, alkalimetal carbonates such lithium carbonate, sodium carbonate, potassiumcarbonate, cesium carbonate and the like, and the like. While the amountof the base to be used varies depending on the kind of the solvent andthe other reaction condition, it is generally about 1 to 10 molequivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (X).

The amount of compound (XIIa) to be used is generally about 1 to 10 molequivalent, preferably about 1 to 3 mol equivalent, per 1 mol ofcompound (X).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xyleneetc.), aliphatic hydrocarbons (hexane, heptane etc.), halogenatedhydrocarbons (dichloromethane, chloroform etc.), ethers (diethyl ether,diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,dimethoxyethane etc.), nitriles (acetonitrile etc.), esters (ethylacetate etc.), amides (dimethylformamide etc.), sulfoxides (dimethylsulfoxide etc.) and the like. These solvent may be used in a mixture oftwo or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about 0 to 200° C.,preferably about 25 to 100° C. While the reaction time varies dependingon the kind of compound (X) or a salt thereof, the reaction temperatureand the like, it is, for example, about 0.5 to 100 hr, preferably about0.5 to 24 hr. when R¹¹ is a methyl group, trimethylsilyldiazomethane maybe used instead of compound (XIIa). The amount of thetrimethylsilyldiazomethane to be used is generally about 1 to 10 molequivalent, preferably about 1 to 3 mol equivalent, per 1 mol ofcompound (X).

This reaction is carried out in a solvent that does not adverselyinfluence the reaction. Examples of the solvent that does not adverselyinfluence the reaction include aromatic hydrocarbons (benzene, toluene,xylene etc.), aliphatic hydrocarbons (hexane, heptane etc.), halogenatedhydrocarbons (dichloromethane, chloroform etc.), ethers (diethyl ether,diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,dimethoxyethane etc.), nitriles (acetonitrile etc.), esters (ethylacetate etc.), amides (dimethylformamide etc.), sulfoxides (dimethylsulfoxide etc.) and the like. These solvent may be used in a mixture oftwo or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about 0 to 50° C.,preferably about 0 to 30° C. While the reaction time varies depending onthe kind of compound (X) or a salt thereof, the reaction temperature andthe like, it is, for example, about 0.5 to 100 hr, preferably about 0.5to 24 hr.

(Step 2)

This step is a step of subjecting compound (XIII) or a salt thereof to adeallylation reaction or a debenzylation reaction to produce compound(XIV) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

(Step 3)

This step is a step of reacting compound (XIV) or a salt thereof withcompound (IV) or a salt thereof in the presence of a condensing agent toproduce compound (XV) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method A.

(Step 4)

This step is a step of subjecting compound (XV) or a salt thereof tohydrolysis to convert compound (XV) or a salt thereof into compound(III) or a salt thereof. This reaction can be carried out according to amethod known per se, generally carried out in the presence of an acid ora base, in a solvent that does not adversely influence the reaction ifnecessary.

Examples of the acid include mineral acids (hydrochloric acid,hydrobromic acid, sulfuric acid etc.), carboxylic acids (acetic acid,trifluoroacetic acid, trichloroacetic acid etc.), sulfonic acids(methanesulfonic acid, p-toluenesulfonic acid etc.), Lewis acids(aluminium chloride, tin chloride, zinc bromide etc.) and the like.These solvent may be used in a mixture of two or more kinds thereof ifnecessary. While the amount of the acid to be used varies depending onthe kind of the solvent and the other reaction condition, it isgenerally about 0.1 mol equivalent or more per 1 mol of compound (XV).The acid may be used as a solvent.

Examples of the base include inorganic bases (alkali metal hydroxidessuch as lithium hydroxide, sodium hydroxide, potassium hydroxide and thelike, alkali metal hydrogencarbonates such as sodium hydrogencarbonate,potassium hydrogencarbonate and the like, alkali metal carbonates suchas sodium carbonate, potassium carbonate and the like, alkoxides such assodium methoxide, sodium ethoxide and the like, etc.) and organic bases(amines such as trimethylamine, triethylamine, diisopropylethylamine andthe like, cyclic amines such as pyridine, 4-dimethylaminopyridine andthe like, etc.) and the like. Among them, sodium hydroxide ispreferable. While the amount of the base to be used varies depending onthe kind of the solvent and the other reaction condition, it isgenerally about 0.1 to 10 mol equivalent, preferably about 1 to 5 molequivalent, per 1 mol of compound (XV).

Examples of the solvent that does not adversely influence the reactioninclude alcohols (methanol, ethanol, propanol, 2-propanol, butanol,isobutanol, t-butanol etc.), hydrocarbons (benzene, toluene, xylene,hexane, heptane etc.), halogenated hydrocarbons (dichloromethane,chloroform etc.), ethers (diethyl ether, diisopropyl ether, t-butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethane etc.), nitriles(acetonitrile etc.), carboxylic acids (acetic acid etc.), amides(dimethylformamide, dimethylacetamide etc.), sulfoxides (dimethylsulfoxide etc.), water and the like. Among them, ethanol,tetrahydrofuran and water are preferable. These solvent may be used in amixture of two or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −50 to 200° C.,preferably about 0 to 100° C. While the reaction time varies dependingon the kind of compound (XV) or a salt thereof, the reaction temperatureand the like, it is, for example, about 0.5 to 100 hr, preferably about0.5 to 24 hr.

When, in compound (I), compound (I′) or compound (I″), Z¹ is atetrahydropyran-4-yl group, L is a bond, and R³ is a hydrogen atom, theraw material in Method A can be produce according to Method D.

wherein each symbol is as defined above.(Step 1)

This step is a step of reacting compound (XVI) with glyoxylic acid anddiallylamine to produce compound (XVII) or a salt thereof.

The compounds used for this reaction may be a commercially availableproduct.

This step can be performed in the same manner as in the method describedin Step 1 of Method B.

(Step 2)

This step is a step of reacting compound (XVII) or a salt thereof withcompound (VI) or a salt thereof in the presence of a condensing agent toproduce compound (XVIII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method A.

(Step 3)

This step is a step of subjecting compound (XVIII) or a salt thereof toa deallylation reaction to produce compound (XIX) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

(Step 4)

This step is a step of subjecting compound (XIX) or a salt thereof to acatalytic hydrogenation reaction to produce compound (XX) or a saltthereof.

The catalytic hydrogenation reaction can be carried out in the presenceof a catalyst under hydrogen atmosphere. Examples of the catalystinclude palladiums such as palladium on carbon, palladium hydroxidecarbon, palladium oxide and the like; nickels such as Raney nickelcatalyst and the like; platinums such as platinum oxide, platinum oncarbon and the like; rhodiums such as rhodium on carbon and the like,and the like. The amount of the catalyst to be used is generally about0.001 to 1 mol, preferably about 0.01 to 0.5 mol, per 1 mol of compound(XIX).

The catalytic hydrogenation reaction is generally carried out in asolvent inert to the reaction. Examples of the solvent include alcoholssuch as methanol, ethanol, propanol, butanol and the like; hydrocarbonssuch as benzene, toluene, xylene and the like; halogenated hydrocarbonssuch as dichloromethane, chloroform and the like; ethers such as diethylether, dioxane, tetrahydrofuran and the like; esters such as ethylacetate and the like; amides such as N,N-dimethylformamide and the like;carboxylic acids such as acetic acid and the like; water and mixturesthereof.

The hydrogen pressure for the reaction is generally about 1 to 50 atm,preferably about 1 to 10 atm. The reaction temperature is generallyabout 0° C. to 150° C., preferably about 20° C. to 100° C., and thereaction time is generally about 5 min to about 72 hr, preferably about0.5 hr to about 40 hr.

When, in compound (I), compound (I′) or compound (I″), Z¹ is atetrahydropyran-4-yl group, L is a bond, and R³ is a substituent, theraw material in Method A can be produce according to Method E.

wherein each symbol is as defined above.(Step 1)

This step is a step of reacting compound (XVI) with glyoxylic acid andcompound (XXI) or a salt thereof to produce compound (XXII) or a saltthereof.

The compounds used for this reaction may be a commercially availableproduct, or can also be produced according to a method known per se or amethod analogous thereto.

This step can be performed in the same manner as in the method describedin Step 1 of Method B.

(Step 2)

This step is a step of reacting compound (XXII) or a salt thereof withcompound (VI) or a salt thereof in the presence of a condensing agent toproduce compound (XXIII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method A.

(Step 3)

This step is a step of subjecting compound (XXIII) or a salt thereof toa debenzylation reaction and a catalytic reduction reaction to producecompound (XXIV) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

When, in compound (I), compound (I′) or compound (I″), Z¹ is atetrahydropyran-4-yl group, L is a bond, and R³ is a hydrogen atom, theraw material in Method A can be produce according to Method F.

wherein Cbz is a carbobenzoxy group, and the other symbols are asdefined above.(Step 1)

This step is a step of reacting compound (XXV) withdihydro-2H-pyran-4(3H)-one in the presence of a base, in a solvent thatdoes not adversely influence this reaction to produce compound (XXVI) ora salt thereof.

The compounds used for this reaction may be a commercially availableproduct.

Examples of the base to be used for this reaction include organic bases(amines such as 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine,diisopropylethylamine and the like), inorganic bases (alkali metalhydrides such as sodium hydride, lithium hydride and the like) and thelike. Among them, 1,8-diazabicyclo[5.4.0]undec-7-ene is preferable.While the amount of the base to be used varies depending on the kind ofthe solvent and the other reaction condition, it is generally about 1 to10 mol equivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (XXV).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons (benzene, toluene, xylene etc.), aliphatichydrocarbons (hexane, heptane etc.), halogenated hydrocarbons(dichloromethane, chloroform etc.), ethers (diethyl ether, diisopropylether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethaneetc.), nitriles (acetonitrile etc.), esters (ethyl acetate etc.), amides(dimethylformamide etc.), sulfoxides (dimethyl sulfoxide etc.) and thelike. These solvent may be used in a mixture of two or more kindsthereof in an appropriate ratio.

The amount of the dihydro-2H-pyran-4(3H)-one to be used is about 1 to 10mol equivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (XXV).

The reaction temperature is, for example, within about −10 to 100° C.,and the reaction time is about 0.5 to 100 hr, preferably about 0.5 to 24hr.

(Step 2)

This step is a step of subjecting compound (XXVI) or a salt thereof tohydrolysis to convert compound (XXVI) or a salt thereof into compound(XXVII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 4 of Method C.

(Step 3)

This step is a step of reacting compound (XXVII) or a salt thereof withcompound (VI) or a salt thereof in the presence of a condensing agent toproduce compound (XXVIII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method A.

(Step 4)

This step is a step of subjecting compound (XXVIII) or a salt thereof toa deprotection reaction and a catalytic reduction reaction to producecompound (XX) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

When, in compound (I), compound (I′) or compound (I″), Z¹ is a4,4-difluorocyclohexan-1-yl group, L is a bond, and R² is a hydrogenatom, the raw material in Method A can be produce according to Method G.

wherein each symbol is as defined above.(Step 1)

This step is a step of reacting compound (XXV) with4,4-difluorocyclohexanone in the presence of a base to produce compound(XXIX) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method F.

(Step 2)

This step is a step of subjecting compound (XXIX) or a salt thereof tohydrolysis to convert compound (XXIX) or a salt thereof into compound(XXX) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 4 of Method C.

(Step 3)

This step is a step of reacting compound (XXX) or a salt thereof withcompound (VI) or a salt thereof in the presence of a condensing agent toproduce compound (XXXI) and compound (XXXIa) or salts thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method A.

(Step 4)

This step is a step of subjecting compound (XXXI) and compound (XXXIa)or salts thereof to a deprotection reaction and a catalytic reductionreaction to produce compound (XXXII) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

When, in compound (I), compound (I′) or compound (I″), Z¹ is anoptionally substituted non-aromatic ring group, L is CH₂, and R³ isoptionally substituted C₁₋₆ alkyl group, the raw material in Method Acan be produce according to Method H.

wherein each symbol is as defined above.(Step 1)

This step is a step of reacting compound (XXV) with compound (XXXIII) ora salt thereof in the presence of a base to produce compound (XXXIV) ora salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method F.

(Step 2)

This step is a step of subjecting compound (XXXIV) or a salt thereof tohydrolysis to convert compound (XXXIV) or a salt thereof into compound(XXXV) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 4 of Method C.

(Step 3)

This step is a step of reacting compound (XXXV) or a salt thereof withcompound (VI) or a salt thereof in the presence of a condensing agent toproduce compound (XXXVI) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 1 of Method A.

(Step 4)

This step is a step of subjecting compound (XXXVI) or a salt thereof toan alkylation reaction with a compound represented by the formula:R³-L  (XXXVII)wherein each symbol is as defined above (hereinafter to be referred toas compound (XXXVII)) or a salt thereof, in the presence of a base, toproduce compound (XXXVIII) or a salt thereof.

Compound (XXXVII) may be a commercially available product, or can alsobe produced according to a method known per se or a method analogousthereto.

Examples of the base to be used for this reaction include inorganicbases (alkali metal hydrides such as sodium hydride, lithium hydride andthe like, alkali metal hydroxides such as lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like, alkali metalhydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate and the like, alkali metal carbonates such as lithiumcarbonate, sodium carbonate, potassium carbonate, cesium carbonate andthe like) and the like. While the amount of the base to be used variesdepending on the kind of the solvent and the other reaction condition,it is generally about 1 to 10 mol equivalent, preferably about 1 to 5mol equivalent, per 1 mol of compound (XXXVI).

The amount of compound (XXXVII) to be used is generally about 1 to 10mol equivalent, preferably about 1 to 3 mol equivalent, per 1 mol ofcompound (XXXVI).

This step is carried out in a solvent that does not adversely influencethe reaction. Examples of the solvent that does not adversely influencethe reaction include aromatic hydrocarbons (benzene, toluene, xyleneetc.), aliphatic hydrocarbons (hexane, heptane etc.), halogenatedhydrocarbons (dichloromethane, chloroform etc.), ethers (diethyl ether,diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,dimethoxyethane etc.), nitriles (acetonitrile etc.), esters (ethylacetate etc.), amides (dimethylformamide etc.), sulfoxides (dimethylsulfoxide etc.) and the like. These solvent may be used in a mixture oftwo or more kinds thereof in an appropriate ratio.

The reaction temperature is, for example, within about −75 to 200° C.,preferably about −10 to 30° C. While the reaction time varies dependingon the kind of compound (XXXVII) or a salt thereof, the reactiontemperature and the like, it is, for example, about 0.5 to 100 hr,preferably about 0.5 to 24 hr.

(Step 5)

This step is a step of subjecting compound (XXXVIII) or a salt thereofto a deprotection reaction to produce compound (IXL) or a salt thereof.

This step can be performed in the same manner as in the method describedin Step 3 of Method B.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (XL)) or a salt thereof, thecompound can be produced according to Method I.

(Step 1)

This step is a step of reacting compound (XLI) with a silylating agentin the absence or presence of a transition metal catalyst to producecompound (XLII).

Compound (XLI) may be a commercially available product.

Examples of the transition metal catalyst to be used for this reactioninclude palladium catalysts (palladium acetate, palladium chloride,tetrakistriphenylphosphine palladium,tris(dibenzylideneacetone)dipalladium(0) etc.), nickel catalysts (nickelchloride etc.) and the like. Where necessary, a ligand(triphenylphosphine, tri-t-butylphosphine, S-Phos, BINAP,2′-(di-tert-butylphosphino)-N, N-dimethyl-[1,1′-biphenyl]-2-amine etc.)and a base (e.g., organic amines (trimethylamine, triethylamine,diisopropylamine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]undec-7-ene, pyridine, N,N-dimethylaniline etc.),alkali metal salts (sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium carbonate, potassium carbonate, cesiumcarbonate, sodium phosphate, potassium phosphate, sodium hydroxide,potassium hydroxide, lithium acetate etc.), metal hydrides (potassiumhydride, sodium hydride etc.), alkali metal alkoxides (sodium methoxide,sodium ethoxide, sodium-t-butoxide, potassium-t-butoxide etc.), alkalidisilazides (lithium disilazide, sodium disilazide, potassium disilazideetc.)) may be added, or a metal oxide (copper oxide, silver oxide, etc.)and the like may be used as a co-catalyst. The amount of the catalyst tobe used is about 0.0001 to 1 mol equivalent, preferably about 0.01 to0.5 mol equivalent, per 1 mol of compound (XLI). The amount of theligand to be used is about 0.0001 to 4 mol equivalent, preferably about0.01 to 2 mol equivalent, per 1 mol of compound (XLI). The amount of thebase to be used is about 1 to 10 mol equivalent, preferably about 1 to 2mol equivalent, per 1 mol of compound (XLI). The amount of theco-catalyst to be used is about 0.0001 to 4 mol equivalent, preferablyabout 0.01 to 2 mol equivalent, per 1 mol of compound (XLI).

The solvent to be used is not particularly limited as long as it doesnot adversely influence the reaction, and examples thereof includehydrocarbons (benzene, toluene, xylene etc.), halogenated hydrocarbons(chloroform, 1,2-dichloroethane etc.), nitriles (acetonitrile etc.),ethers (dimethoxyethane, tetrahydrofuran), alcohols (methanol, ethanoletc.), aprotic polar solvents (dimethylformamide, dimethyl sulfoxide,hexamethylphosphoroamide etc.), water and mixtures thereof. The reactiontemperature is generally about −100 to 200° C., preferably about −80 to150° C., and the reaction time is generally about 0.5 to 48 hr,preferably about 0.5 to 24 hr. The reaction may be carried out undermicrowave irradiation, if necessary.

Examples of the silylating agent include 1,1,1,2,2,2-hexamethyldisilaneand chlorotrimethylsilane.

(Step 2)

This step is a step of subjecting compound (XLII) to a reductionreaction using a transition metal catalyst to produce compound (XL).

Examples of the transition metal catalyst to be used for this reactioninclude palladiums (palladium on carbon, palladium hydroxide, palladiumoxide etc.), nickels (Raney nickel etc.), platinums (platinum oxide,platinum on carbon etc.), rhodiums (rhodium acetate, rhodium on carbonetc.) and the like. The amount of the transition metal catalyst to beused is, for example, about 0.001 to 1 equivalent, preferably about 0.01to 0.5 equivalent, per 1 mol of compound (XLII). The catalytichydrogenation reaction is generally carried out in a solvent inert tothe reaction. Examples of the solvent include alcohols (methanol,ethanol, propanol, butanol etc.), hydrocarbons (benzene, toluene, xyleneetc.), halogenated hydrocarbons (dichloromethane, chloroform etc.),ethers (diethyl ether, dioxane, tetrahydrofuran etc.), esters (ethylacetate etc.), amides (N,N-dimethylformamide etc.), carboxylic acids(acetic acid etc.), water and mixtures thereof. The hydrogen pressurefor the reaction is generally about 1 to 500 atm, preferably about 1 to100 atm. The reaction temperature is generally about 0 to 150° C.,preferably about 20 to 100° C., and the reaction time is generally about5 min to 72 hr, preferably about 0.5 to 40 hr.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (XLIII)) or a salt thereof,the compound can be produced according to Method J.

(Step 1)

This step is a step of reacting compound (XLIV) with a silylating agentin the presence of a transition metal catalyst to produce compound(XLV).

Compound (XLIV) may be a commercially available product.

This step can be performed in the same manner as in the method describedin Step 1 of Method I.

(Step 2)

This step is a step of subjecting compound (XLV) to a reduction reactionusing a transition metal catalyst to produce compound (XLIII).

This step is can be performed in the same manner as in the methoddescribed in Step 2 of Method I, or by a reduction reaction using ametal (e.g., iron).

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (XLVI)) or a salt thereof,the compound can be produced according to Method K.

(Step 1)

This step is a step of reacting compound (XLVII) with a silylating agentin the presence of a transition metal catalyst to produce compound(XLVIII).

Compound (XLVII) may be a commercially available product.

This step can be performed in the same manner as in the method describedin Step 1 of Method I.

(Step 2)

This step is a step of subjecting compound (XLVIII) to a reductionreaction using a transition metal catalyst to produce compound (XLVI).

This step can be performed in the same manner as in the method describedin Step 2 of Method I.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (XLIX)) or a salt thereof,the compound can be produced according to Method L.

(Step 1)

This step is a step of reacting compound (L) with a silylating agent inthe presence of a transition metal catalyst to produce compound (LI).

Compound (L) may be a commercially available product.

This step can be performed in the same manner as in the method describedin Step 1 of Method I.

(Step 2)

This step is a step of subjecting compound (LI) to a reduction reactionusing a transition metal catalyst to produce compound (XLIX).

This step can be performed in the same manner as in the method describedin Step 2 of Method I.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (LII)) or a salt thereof, thecompound can be produced according to Method M.

(Step 1)

This step is a step of reacting compound (LIII) with a silylating agentin the presence of an organic lithium reagent to produce compound (LIV).

Compound (LIII) may be a commercially available product.

Examples of the organic lithium reagent to be used includen-butyllithium, phenyllithium and the like.

While the amount of the organic lithium reagent to be used variesdepending on the kind of the solvent and the other reaction condition,it is generally about 1 to 10 mol equivalent, preferably about 1 to 5mol equivalent, per 1 mol of compound (LIII).

Examples of the silylating agent include 1,1,1,2,2,2-hexamethyldisilaneand chlorotrimethylsilane.

This step is generally carried out in a solvent that does not adverselyinfluence the reaction. Examples of the solvent include hydrocarbons(benzene, toluene etc.), ethers (diethyl ether, dioxane, tetrahydrofuranetc.) and the like, and they may be mixed as appropriate. Among them,tetrahydrofuran is preferable.

The reaction temperature is generally about −200 to 40° C., preferablyabout −80 to 5° C., and the reaction time is generally about 0.0001 to12 hr, preferably about 0.0001 to 1 hr.

(Step 2)

This step is a step of subjecting compound (LIV) to a reduction reactionusing a transition metal catalyst to produce compound (LII).

This step can be performed in the same manner as in the method describedin Step 2 of Method I.

When compound (VI) is a compound represented by the formula:

(hereinafter to be referred to as compound (LV)) or a salt thereof, thecompound can be produced according to Method N.

This step is a step of reacting compound (LVI) with t-butylmagnesiumchloride or t-butylmagnesium bromide in the presence of copper cyanideand lithium chloride to produce compound (LVII).

Compound (LVI) may be a commercially available product.

The amount of the copper cyanide to be used is about 1 to 10 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (LVI).

The amount of the lithium chloride to be used is about 1 to 10 molequivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (LVI).

The amount of the t-butylmagnesium chloride or t-butylmagnesium bromideto be used is about 1 to 5 mol equivalent, preferably about 1 to 2 molequivalent, per 1 mol of compound (LVI).

This step is generally carried out in a solvent that does not adverselyinfluence the reaction. Examples of the solvent include hydrocarbons(benzene, toluene etc.), ethers (diethyl ether, dioxane, tetrahydrofuranetc.) and the like, and they may be mixed as appropriate. Among them,tetrahydrofuran is preferable.

The reaction temperature is generally about −200 to 40° C., preferablyabout −80 to 5° C., and the reaction time is generally about 0.1 to 12hr, preferably about 0.1 to 1 hr.

(Step 2)

This step is a step of subjecting compound (LVII) to a reductionreaction using triethylsilane and trifluoroacetic acid to producecompound (LVIII).

The amount of the triethylsilane to be used is about 1 to 10 molequivalent, preferably about 1 to 2 mol equivalent, per 1 mol ofcompound (LVII).

The amount of the trifluoroacetic acid to be used is about 1 to 10 molequivalent, preferably about 1 to 5 mol equivalent, per 1 mol ofcompound (LVII). Trifluoroacetic acid can be used as a solvent.

The reaction temperature is generally about −20 to 100° C., preferablyabout 0 to 30° C., and the reaction time is generally about 1 to 100 hr,preferably about 1 to 72 hr.

(Step 3)

This step is a step of reacting compound (LVIII) with an aminating agentin the presence of a transition metal catalyst and a base, and thentreating the resulting compound with hydroxylamine hydrochloride andsodium acetate to produce compound (LV).

The kinds and amounts of the transition metal catalyst and base to beused are the same as in Step 1 of Method I.

Preferable examples of the aminating agent to be used includediphenylmethanimine. The amount of the aminating agent to be used isabout 1 to 5 mol equivalent, preferably about 1 to 2 mol equivalent, per1 mol of compound (LVII).

The kind of the solvent to be used for the reaction with an aminatingagent, and the reaction temperature are the same as in Step 1 of MethodI.

The amounts of the hydroxylamine hydrochloride and sodium acetate to beused are about 1 to 5 mol equivalent, preferably about 1 to 2 molequivalent, per 1 mol of compound (LVII), respectively.

Preferable examples of the solvent to be used for the treatment withhydroxylamine hydrochloride and sodium acetate include methanol. Thereaction temperature is about −20 to 100° C., preferably about 0 to 30°C., and the reaction time is generally about 1 to 100 hr, preferablyabout 1 to 72 hr.

When the object product is obtained in a free form by theabove-mentioned reaction, it may be converted to a salt by aconventional method. When it is obtained as a salt, it can also beconverted to a free form or other salt by a conventional method. Thethus-obtained compound (I), compound (I′) or compound (I″) can beisolated and purified from the reaction solution by a known means, forexample, phase transfer, concentration, solvent extraction,fractionation, crystallization, recrystallization, chromatography andthe like.

When compound (I), compound (I′) or compound (I″) contains an isomersuch as a tautomer, an optical isomer, a stereoisomer, a regioisomer, arotamer and the like, any isomer and a mixture thereof are alsoencompassed in the compound of the present invention. Furthermore, whencompound (I), compound (I′) or compound (I″) has an optical isomer, anoptical isomer resolved from this compound is also encompassed incompound (I), compound (I′) or compound (I″).

Compound (I), compound (I′) or compound (I″) may be a crystal. Even ifcompound (I), compound (I′) or compound (I″) is in a single crystal formor mixed crystal form, it can be provided as compound (I), compound (I′)or compound (I″).

Compound (I), compound (I′) or compound (I″) may be a pharmaceuticallyacceptable co-crystal or co-crystal salt. Here, the co-crystal orco-crystal salt means a crystalline substance consisting of two or moreparticular substances which are solids at room temperature, each ofwhich has different physical properties (e.g., structure, melting point,heat of melting, hygroscopicity, solubility, stability etc.). Thecocrystal and cocrystal salt can be produced by cocrystallization knownper se.

Compound (I), compound (I′) or compound (I″) may be a solvate (e.g., ahydrate) or a nonsolvate (e.g., non-hydrate, etc.). Any of them can beprovided as compound (I), compound (I′) or compound (I″).

Any of the above compounds may be labeled or substituted with an isotope(e.g., ²H, ³H, ¹¹C, ¹⁴C, ¹⁸F, ³⁵S, or ¹²⁵I) and provided as compound(I), compound (I′) or compound (I″). Compound (I), compound (I′) orcompound (I″) labeled or substituted with an isotope can be used, forexample, as a tracer (PET tracer) used for positron emission tomography(PET), and is useful in the field such as medical diagnosis and thelike.

The prodrug of compound (I), compound (I′) or compound (I″) means acompound which can be converted into compound (I), compound (I′) orcompound (I″) by reaction with an enzyme, gastric acid, or the likeunder physiological conditions in the living body. In other words, itmeans a compound which can be converted into compound (I), compound (I′)or compound (I″) by enzymatic oxidation, reduction, hydrolysis or thelike, or a compound which can be converted into compound (I), compound(I′) or compound (I″) by hydrolysis with gastric acid or the like.Examples of the prodrug of compound (I), compound (I′) or compound (I″)include a compound in which amino of compound (I), compound (I′) orcompound (I″) is acylated, alkylated, or phosphorylated (e.g., the aminoof compound (I), compound (I′) or compound (I″) is eicosanoylated,alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, ortert-butylated); a compound in which hydroxyl of compound (I), compound(I′) or compound (I″) is acylated, alkylated, phosphorylated, or borated(e.g., hydroxyl of compound (I), compound (I′) or compound (I″) isacetylated, palmitoylated, propanoylated, pivaloylated, succinylated,fumarylated, alanylated, or dimethylaminomethylcarbonylated); a compoundin which carboxy of compound (I), compound (I′) or compound (I″) isesterified or amidated (e.g., a compound in which carboxy of compound(I), compound (I′) or compound (I″) is ethyl esterified, phenylesterified, carboxymethyl esterified, dimethylaminomethyl esterified,pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified,phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterified, cyclohexyloxycarbonylethyl esterified, or methylamidated).These compounds can be produced from compound (I), compound (I′) orcompound (I″) by a method known per se.

The prodrug of compound (I), compound (I′) or compound (I″) may be acompound that converts to compound (I), compound (I′) or compound (I″)under physiological conditions as described in Development ofPharmaceutical Products, vol. 7, Molecule Design, 163-198, HirokawaShoten (1990).

Since compound (I), compound (I′) and compound (I″) and a prodrugthereof [hereinafter sometimes to be abbreviated as the compound of thepresent invention] show superior RORγt inhibitory activity, they arealso useful as safe medicaments based on such action.

For example, the medicament of the present invention containing thecompound of the present invention can be used for a mammal (e.g., mouse,rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) as aprophylactic or therapeutic agent for RORγt associated diseases, Th17cell associated diseases and IL-17A or IL-17F associated diseases, morespecifically, the diseases described in (1)-(4) below.

(1) inflammatory diseases (e.g., rheumatoid arthritis, acutepancreatitis, chronic pancreatitis, asthma, bronchial asthma, adultrespiratory distress syndrome, chronic obstructive pulmonary disease(COPD), inflammatory bone disease, inflammatory pulmonary disease,inflammatory bowel disease, celiac disease, hepatitis, systemicinflammatory response syndrome (SIRS), postoperative or posttraumaticinflammation, pneumonia, nephritis, meningitis, cystitis,pharyngolaryngitis, gastric mucosal injury, spondylitis, arthritis,dermatitis, chronic pneumonia, bronchitis, pulmonary infarction,silicosis, pulmonary sarcoidosis, uveitis etc.),(2) autoimmune diseases (e.g., rheumatoid arthritis, ankylosingspondylitis, psoriasis, multiple sclerosis (MS), polymyositis,dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissuedisease (MCTD), Sjogren's syndrome, systemic lupus erythematosus (SLE),scleroderma, profundus lupus erythematosus, chronic thyroiditis, Graves'disease, autoimmune gastritis, type I and type II diabetes, autoimmunehemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopicdermatitis, chronic active hepatitis, myasthenia gravis, inflammatorybowel disease (IBD), ulcerative colitis (UC), Crohn's disease, graftversus host disease, Addison's disease, abnormal immunoresponse,arthritis, dermatitis, radiodermatitis etc.),(3) bone or joint degenerative diseases (e.g., rheumatoid arthritis,osteoporosis, osteoarthritis etc.),(4) neoplastic diseases [e.g., malignant tumor, angiogenesis glaucoma,infantile hemangioma, multiple myeloma, acute myeloblastic leukemia,chronic sarcoma, multiple myeloma, chronic myelogenous leukemia,metastasis melanoma, Kaposi's sacroma, vascular proliferation, cachexia,metastasis of the breast cancer, cancer (e.g., colorectal cancer (e.g.,familial colorectal cancer, hereditary nonpolyposis colorectal cancer,gastrointestinal stromal tumor and the like), lung cancer (e.g.,non-small cell lung cancer, small cell lung cancer, malignantmesothelioma and the like), mesothelioma, pancreatic cancer (e.g.,pancreatic duct cancer and the like), gastric cancer (e.g., papillaryadenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma and thelike), breast cancer (e.g., invasive ductal carcinoma, ductal carcinomain situ, inflammatory breast cancer and the like), ovarian cancer (e.g.,ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germcell tumor, ovarian low malignant potential tumor and the like),prostate cancer (e.g., hormone-dependent prostate cancer, non-hormonedependent prostate cancer and the like), liver cancer (e.g., primaryliver cancer, extrahepatic bile duct cancer and the like), thyroidcancer (e.g., medullary thyroid carcinoma and the like), kidney cancer(e.g., renal cell carcinoma, transitional cell carcinoma in kidney andurinary duct and the like), uterine cancer, endometrial cancer, braintumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuseastrocytoma, anaplastic astrocytoma and the like), melanoma (melanoma),sarcoma, urinary bladder cancer, hematologic cancer and the likeincluding multiple myeloma, hypophyseal adenoma, glioma, acousticneurinoma, retinoblastoma, head and neck cancer, pharyngeal cancer,laryngeal cancer, cancer of the tongue, thymoma, esophagus cancer,duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreaticendocrine tumor, cancer of the bile duct, gallbladder cancer, penilecancer, urinary duct cancer, testis tumor, vulvar cancer, cervix cancer,endometrial cancer, uterus sarcoma, cholionic disease, vaginal cancer,skin cancer, fungoid mycosis, basal cell tumor, soft tissue sarcoma,malignant lymphoma, Hodgkin's disease, myelodysplastic syndrome, acutelymphocytic leukemia, chronic lymphocytic leukemia, adult T cellleukemia, chronic bone marrow proliferative disease, pancreaticendocrine tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma,cancer of unknown primary).

The medicament of the present invention can be preferably used as anagent for the prophylaxis or treatment of psoriasis, inflammatory boweldisease (IBD), ulcerative colitis (UC), Crohn's disease (CD), rheumatoidarthritis, multiple sclerosis, uveitis, asthma, ankylopoieticspondylarthritis, systemic lupus erythematosus (SLE) and the like.

In another embodiment, the medicament of the present invention can bepreferably used as an agent for the prophylaxis or treatment ofautoimmune disease, inflammatory disease, bone or articular disease, orneoplastic disease, particularly preferably psoriasis, inflammatorybowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD),rheumatoid arthritis, multiple sclerosis, uveitis, asthma, ankylopoieticspondylarthritis, systemic lupus erythematosus (SLE), chronicobstructive pulmonary diseases, ovarian cancer, non small cell lungcancer, breast cancer, stomach cancer, head and neck cancer, prostatecancer or endometrial cancer.

Here, the above-mentioned “prophylaxis” of a disease means, for example,administration of a medicament containing the compound of the presentinvention to patients who are expected to have a high risk of the onsetdue to some factor relating to the disease but have not developed thedisease or patients who have developed the disease but do not have asubjective symptom, or administration of a medicament containing thecompound of the present invention to patients who are feared to showrecurrence of the disease after treatment of the disease.

The medicament of the present invention shows superior pharmacokinetics(e.g., a half-life of the drug in plasma), low toxicity (e.g., HERGinhibition, CYP inhibition, CYP induction), and decreased druginteraction. The compound of the present invention can be directly usedas a medicament, or as the medicament of the present invention byproducing a pharmaceutical composition by mixing with a pharmaceuticallyacceptable carrier by a means known per se and generally used in aproduction method of pharmaceutical preparations. The medicament of thepresent invention can be orally or parenterally administered safely tomammals (e.g., humans, monkeys, cows, horses, pigs, mice, rats,hamsters, rabbits, cats, dogs, sheep and goats).

A medicament containing the compound of the present invention can besafely administered solely or by mixing with a pharmacologicallyacceptable carrier according to a method known per se (e.g., the methoddescribed in the Japanese Pharmacopoeia etc.) as the production methodof a pharmaceutical preparation, and in the form of, for example, tablet(including sugar-coated tablet, film-coated tablet, sublingual tablet,orally disintegrating tablet, buccal and the like), pill, powder,granule, capsule (including soft capsule, microcapsule), troche, syrup,liquid, emulsion, suspension, release control preparation (e.g.,immediate-release preparation, sustained-release preparation,sustained-release microcapsule), aerosol, film (e.g., orallydisintegrating film, oral mucosa-adhesive film), injection (e.g.,subcutaneous injection, intravenous injection, intramuscular injection,intraperitoneal injection), drip infusion, transdermal absorption typepreparation, ointment, lotion, adhesive preparation, suppository (e.g.,rectal suppository, vaginal suppository), pellet, nasal preparation,pulmonary preparation (inhalant), eye drop and the like, orally orparenterally (e.g., intravenous, intramuscular, subcutaneous,intraorgan, intranasal, intradermal, instillation, intracerebral,intrarectal, intravaginal, intraperitoneal and intratumoradministrations, administration to the vicinity of tumor, and directadministration to the lesion).

The content of the compound of the present invention in the medicamentof the present invention is about 0.01 to 100% by weight of the entiremedicament. While the dose varies depending on the subject ofadministration, administration route, disease and the like, for example,for oral administration to an adult inflammatory bowel disease (IBD)patient (body weight about 60 kg), it is about 0.1 mg/kg body weight to30 mg/kg body weight, preferably about 1 mg/kg body weight to 20 mg/kgbody weight as an active ingredient (compound (I), compound (I′) orcompound (I″)) for one day, which is administered once to several times,preferably once or two to three times.

The pharmaceutically acceptable carrier, which may be used for theproduction of the medicament of the present invention, may beexemplified by various organic or inorganic carrier materials that areconventionally used as preparation materials, for example, excipient,lubricant, binding agent and disintegrant for solid preparations; orsolvent, solubilizing agent, suspending agent, isotonic agent, bufferingagent, soothing agent and the like for liquid preparations. Furthermore,when necessary, ordinary additives such as preservative, antioxidant,colorant, sweetening agent, adsorbing agent, wetting agent and the likecan be also used as appropriate in an appropriate amount.

Examples of the excipient include lactose, white sugar, D-mannitol,starch, corn starch, crystalline cellulose, light anhydrous silicic acidand the like.

Examples of the lubricant include magnesium stearate, calcium stearate,talc, colloidal silica and the like.

Examples of the binding agent include crystalline cellulose, whitesugar, D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose,gelatin, methylcellulose, carboxymethylcellulose sodium and the like.

Examples of the disintegrant include starch, carboxymethylcellulose,carboxymethylcellulose calcium, carboxymethylstarch sodium,L-hydroxypropylcellulose and the like.

Examples of the solvent include water for injection, alcohol, propyleneglycol, Macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the solubilizing agent include polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzetonium chloride, glycerinmonostearate and the like; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; and the like.

Examples of the isotonic agent include glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol and the like.

Examples of the buffering agent include buffer solutions such asphosphates, acetates, carbonates, citrates and the like.

Examples of the soothing agent include benzyl alcohol and the like.

Examples of the preservative include parahydroxybenzoates,chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid,sorbic acid and the like.

Examples of the antioxidant include sulfites, ascorbic acid,α-tocopherol and the like.

For the prophylaxis or treatment of various diseases, the compound ofthe present invention can also be used together with other medicaments.In the following, a medicament to be used when the compound of thepresent invention is used together with other drug is referred to as“the combination agent of the present invention”.

For example, when the compound of the present invention is used as anRORγt inhibitor, Th17 cell inhibitor, IL-17A or IL-17F inhibitor, it canbe used in combination with the following drugs.

(1) Non-Steroidal Anti-Inflammatory Drug (NSAIDs)

(i) Classical NSAIDs

alcofenac, aceclofenac, sulindac, tolmetin, etodolac, fenoprofen,thiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lornoxicam,nabumeton, acetaminophen, phenacetin, ethenzamide, sulpyrine,antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid,diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin,ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen,pranoprofen, floctafenine, piroxicam, epirizole, tiaramidehydrochloride, zaltoprofen, gabexate mesylate, camostat mesylate,ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone,allopurinol, sodium aurothiomalate, hyaluronate sodium, sodiumsalicylate, morphine hydrochloride, salicylic acid, atropine,scopolamine, morphine, pethidine, levorphanol, oxymorphone or a saltthereof and the like.

(ii) Cyclooxygenase Inhibitor (COX-1 Selective Inhibitor, COX-2Selective Inhibitor and the Like)

salicylic acid derivatives (e.g., celecoxib, aspirin), etoricoxib,valdecoxib, diclofenac, indomethacin, loxoprofen and the like.

(iii) Nitric Oxide-Releasing NSAIDs

(2) Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

(i) Gold Preparation

auranofin and the like.

(ii) penicillamine

D-penicillamine.

(iii) Aminosalicylic Acid Preparation

sulfasalazine, mesalazine, olsalazine, balsalazide.

(iv) Antimalarial Drug

chloroquine and the like.

(v) pyrimidine synthesis inhibitor

leflunomide and the like.

(vi) tacrolimus

(3) Anti-Cytokine Drug

(I) Protein Drug

(i) TNF Inhibitor

etanercept, infliximab, adalimumab, certolizumab pegol, golimumab,PASSTNF-α, soluble TNF-α receptor, TNF-α binding protein, anti-TNF-αantibody and the like.

(ii) Interleukin-1 Inhibitor

anakinra (interleukin-1 receptor antagonist), soluble interleukin-1receptor and the like.

(iii) Interleukin-6 Inhibitor

tocilizumab (anti-interleukin-6 receptor antibody), anti-interleukin-6antibody and the like.

(iv) Interleukin-10 Drug

interleukin-10 and the like.

(v) Interleukin-12/23 Inhibitor

ustekinumab, briakinumab (anti-interleukin-12/23 antibody) and the like.

(vi) B Cell Activation Inhibitor

rituxan, benrista and the like.

(vii) Co-Stimulatory Molecules Related Protein Drug

abatacept and the like.

(II) Non-Protein Drug

(i) MAPK Inhibitor

BMS-582949 and the like.

(ii) Gene Modulator

inhibitor of molecule involved in signal transduction, such as NF-κ,NF-κB, IKK-1, IKK-2, AP-1 and the like, and the like.

(iii) Cytokine Production Inhibitor

iguratimod, tetomilast and the like.

(iv) TNF-α converting enzyme inhibitor

(v) interleukin-1β converting enzyme inhibitor

belnacasan and the like.

(vi) Interleukin-6 Antagonist

HMPL-004 and the like.

(vii) Interleukin-8 Inhibitor

IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparixin and the like.

(viii) Chemokine Antagonist

CCR9 antagonist (vercirnon (vercirnon sodium), CCX025,N-{4-chloro-2-[(1-oxidepyridin-4-yl)carbonyl]phenyl}-4-(propan-2-yloxy)benzenesulfonamide),MCP-1 antagonist and the like.

(ix) Interleukin-2 Receptor Antagonist

denileukin, diftitox and the like.

(x) therapeutic vaccines

TNF-α vaccine and the like.

(xi) Gene Therapy Drug

gene therapy drugs aiming at promoting the expression of gene having ananti-inflammatory action such as interleukin-4, interleukin-10, solubleinterleukin-1 receptor, soluble TNF-α receptor and the like.

(xii) Antisense Compound

ISIS 104838 and the like.

(4) Integrin Inhibitor

natalizumab, vedolizumab, AJM300, TRK-170, E-6007 and the like.

(5) Immunomodulator (Immunosuppressant)

methotrexate, cyclophosphamide, MX-68, atiprimod dihydrochloride,abatacept, CKD-461, rimexolone, cyclosporine, tacrolimus, gusperimus,azathiopurine, antilymphocyte serum, freeze-dried sulfonated normalimmunoglobulin, erythropoietin, colony stimulating factor, interleukin,interferon and the like.

(6) Proteasome Inhibitor

velcade and the like.

(7) JAK Inhibitor

tofacitinib and the like.

(8) Steroid

dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone,triamcinolone acetonide, fluocinonide, fluocinolone acetonide,predonisolone, methylpredonisolone, cortisone acetate, hydrocortisone,fluorometholone, beclomethasone dipropionate, estriol and the like.

(9) Angiotensin Converting Enzyme Inhibitor

enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril andthe like.

(10) Angiotensin II Receptor Antagonist

candesartan cilexetil, valsartan, irbesartan, olmesartan, eprosartan andthe like.

(11) Diuretic Drug

hydrochlorothiazide, spironolactone, furosemide, indapamide,bendrofluazide, cyclopenthiazide and the like.

(12) Cardiotonic Drug

digoxin, dobutamine and the like.

(13) β Receptor Antagonist

carvedilol, metoprolol, atenolol and the like.

(14) Ca Sensitizer

caldaret hydrate and the like.

(15) Ca Channel Antagonist

nifedipine, diltiazem, verapamil and the like.

(16) Anti-Platelet Drug, Anticoagulator

heparin, aspirin, warfarin and the like.

(17) HMG-CoA Reductase Inhibitor

atorvastatin, simvastatin and the like.

(18) Contraceptive

(i) Sex Hormone or Derivatives Thereof

gestagen or a derivative thereof (progesterone, 17α-hydroxyprogesterone, medroxyprogesterone, medroxyprogesterone acetate,norethisterone, norethisterone enanthate, norethindrone, norethindroneacetate, norethynodrel, levonorgestrel, norgestrel, ethynodioldiacetate, desogestrel, norgestimate, gestodene, progestin,etonogestrel, drospirenone, dienogest, trimegestone, nestorone,chlormadinone acetate, mifepristone, nomegestrol acetate, tosagestin,TX-525, ethinylestradiol/TX525) or a combination agent of a gestagen ora derivative thereof and an estrogen or a derivative thereof (estradiol,estradiol benzoate, estradiol cypionate, estradiol dipropionate,estradiol enanthate, estradiol hexahydrobenzoate, estradiolphenylpropionate, estradiol undecanoate, estradiol valerate, estrone,ethinylestradiol, mestranol) and the like.

(ii) Antiestrogen

ormeloxifene, mifepristone, Org-33628 and the like.

(iii) Spermatocide

ushercell and the like.

(19) Others

(i) T Cell Inhibitors

(ii) Inosine Monophosphate Dehydrogenase (IMPDH) Inhibitor

mycophenolate mofetil and the like.

(iii) Adhesion Molecule Inhibitor

alicaforsen sodium, selectin inhibitor, ELAM-1 inhibitor, VCAM-1inhibitor, ICAM-1 inhibitor and the like.

(iv) Thalidomide

(v) Cathepsin Inhibitor

(vi) Matrix Metalloprotease (MMPs) Inhibitor

V-85546 and the like.

(vii) Glucose-6-Phosphate Dehydrogenase Inhibitor

(viii) Dihydroorotate Dehydrogenase (DHODH) Inhibitor

(ix) Phosphodiesterase IV (PDE IV) Inhibitor

roflumilast, apremilast, CG-1088 and the like.

(x) Phospholipase A₂ Inhibitor

(xi) iNOS Inhibitor

VAS-203 and the like.

(xii) Microtubule Stimulating Drug

paclitaxel and the like.

(xiii) Microtuble Inhibitor

reumacon and the like.

(xiv) MHC Class II Antagonist

(xv) Prostacyclin Agonist

iloprost and the like.

(xvi) CD4 Antagonist

zanolimumab and the like.

(xvii) CD23 Antagonist

(xviii) LTB4 Receptor Antagonist

DW-1350 and the like.

(xix) 5-Lipoxygenase Inhibitor

zileuton and the like.

(xx) Cholinesterase Inhibitor

galanthamine and the like.

(xxi) Tyrosine Kinase Inhibitor

Tyk2 inhibitor (WO2010/142752) and the like.

(xxii) Cathepsin B Inhibitor

(xxiii) Adenosine Deaminase Inhibitor

pentostatin and the like.

(xxiv) Osteogenesis Stimulator

(xxv) Dipeptidylpeptidase Inhibitor

(xxvi) Collagen Agonist

(xxvii) Capsaicin Cream

(xxviii) Hyaluronic Acid Derivative

synvisc (hylan G-F 20), orthovisc and the like.

(xxix) Glucosamine Sulfate

(xxx) amiprilose

(xxxi) CD-20 inhibitor

rituximab, ibritumomab, tositumomab, ofatumumab and the like.

(xxxii) BAFF Inhibitor

belimumab, tabalumab, atacicept, blisibimod and the like.

(xxxiii) CD52 Inhibitor

alemtuzumab and the like.

Other concomitant drugs besides the above-mentioned include for example,antibacterial agent, antifungal agent, antiprotozoal agent, antibiotic,antitussive and expectorant drug, sedative, anesthetic, antiulcer drug,antiarrhythmic agent, hypotensive diuretic drug, anticoagulant,tranquilizer, antipsychotic, antitumor drug, hypolipidemic drug, musclerelaxant, antiepileptic drug, antidepressant, antiallergic drug, cardiacstimulants, therapeutic drug for arrhythmia, vasodilator,vasoconstrictor, therapeutic drug for diabetes, antinarcotic, vitamin,vitamin derivative, antiasthmatic, therapeutic agent forpollakisuria/anischuria, therapeutic agent for atopic dermatitis,therapeutic agent for allergic rhinitis, hypertensor,endotoxin-antagonist or -antibody, signal transduction inhibitor,inhibitor of inflammatory mediator activity, antibody to inhibitinflammatory mediator activity, inhibitor of anti-inflammatory mediatoractivity, antibody to inhibit anti-inflammatory mediator activity andthe like. Specific examples thereof include the following.

(1) Antibacterial Agent

(i) Sulfa Drug

sulfamethizole, sulfisoxazole, sulfamonomethoxine, salazosulfapyridine,silver sulfadiazine and the like.

(ii) Quinolone Antibacterial Agent

nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin,ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride,lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.

(iii) Antiphthisic

isoniazid, ethambutol (ethambutol hydrochloride), p-aminosalicylic acid(calcium p-aminosalicylate), pyrazinamide, ethionamide, protionamide,rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and thelike.

(iv) Antiacidfast Bacterium Drug

diaphenylsulfone, rifampicin and the like.

(v) Antiviral Drug

idoxuridine, acyclovir, vidarabine, gancyclovir and the like.

(vi) anti-HIV agent

zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate,ritonavir and the like.

(vii) Antispirochetele

(viii) Antibiotic

tetracycline hydrochloride, ampicillin, piperacillin, gentamicin,dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin,sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline,ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin,cephaloridine, cefaclor, cephalexin, cefroxadine, cefadroxil,cefamandole, cefotoam, cefuroxime, cefotiam, cefotiam hexetil,cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime,cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome,cefozopran, cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox,cefoxitin, cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime,cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin,aztreonam or a salt a salt thereof, griseofulvin, lankacidin-group[Journal of Antibiotics (J. Antibiotics), 38, 877-885(1985)], azolecompound[2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone,fluconazole, itraconazole and the like] and the like.

(2) Antifungal Agent

(i) polyethylene antibiotic (e.g., amphotericin B, nystatin,trichomycin)

(ii) griseofulvin, pyrrolnitrin and the like

(iii) cytosine metabolism antagonist (e.g., flucytosine)

(iv) imidazole derivative (e.g., econazole, clotrimazole, miconazolenitrate, bifonazole, croconazole)

(v) triazole derivative (e.g., fluconazole, itraconazole)

(vi) thiocarbamic acid derivative (e.g., trinaphthol) and the like.

(3) Antiprotozoal Agent

metronidazole, tinidazole, diethylcarbamazine citrate, quininehydrochloride, quinine sulfate and the like.

(4) Antitussive and Expectorant Drug

ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate,dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrinehydrochloride, methylephedrine hydrochloride, noscapine hydrochloride,alloclamide, chlophedianol, picoperidamine, cloperastine, protokylol,isoproterenol, salbutamol, terbutaline oxymetebanol, morphinehydrochloride, dextromethorfan hydrobromide, oxycodone hydrochloride,dimemorphan phosphate, tipepidine hibenzate, pentoxyverine citrate,clofedanol hydrochloride, benzonatate, guaifenesin, bromhexinehydrochloride, ambroxol hydrochloride, acetylcysteine, ethyl cysteinehydrochloride, carbocysteine and the like.

(5) Sedative

chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital,amobarbital, pentobarbital, thiopental sodium, thiamylal sodium,nitrazepam, estazolam, flurazepam, haloxazolam, triazolam,flunitrazepam, bromovalerylurea, chloral hydrate, triclofos sodium andthe like.

(6) Anesthetic

(6-1) Local Anesthetic

cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucainehydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride,bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethylaminobenzoate, oxethazaine and the like. (6-2) general anesthetic

(i) inhalation anesthetic (e.g., ether, halothane, nitrous oxide,isoflurane, enflurane),

(ii) intravenous anesthetic (e.g., ketamine hydrochloride, droperidol,thiopental sodium, thiamylal sodium, pentobarbital) and the like.

(7) Antiulcer Drug

histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine,cimetidine, ranitidine, famotidine, urogastrone, oxethazaine,proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate,aldioxa, teprenone, prostaglandin and the like.

(8) Antiarrhythmic Agent

(i) sodium channel blocker (e.g., quinidine, procainamide, disopyramide,ajmaline, lidocaine, mexiletine, phenytoin),

(ii) β-blocker (e.g., propranolol, alprenolol, bufetolol hydrochloride,oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol,carteolol, arotinolol hydrochloride),

(iii) potassium channel blocker (e.g., amiodarone),

(iv) calcium channel blocker (e.g., verapamil, diltiazem) and the like.

(9) Hypotensive Diuretic Drug

hexamethonium bromide, clonidine hydrochloride, hydrochlorothiazide,trichlormethiazide, furosemide, ethacrynic acid, bumetanide, mefruside,azosemide, spironolactone, potassium canrenoate, triamterene, amiloride,acetazolamide, D-mannitol, isosorbide, aminophylline and the like.

(10) Anticoagulant

heparin sodium, sodium citrate, activated protein C, tissue factorpathway inhibitor, antithrombin III, dalteparin sodium, warfarinpotassium, argatroban, gabexate, sodium citrate, ozagrel sodium, ethylicosapentate, beraprost sodium, alprostadil, ticlopidine hydrochloride,pentoxifylline, dipyridamole, tisokinase, urokinase, streptokinase andthe like.

(11) Tranquilizer

diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam,cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzineand the like.

(12) Antipsychotic

chlorpromazine hydrochloride, prochlorperazine, trifluoperazine,thioridazine hydrochloride, perphenazine maleate, fluphenazineenanthate, prochlorperazine maleate, levomepromazine maleate,promethazine hydrochloride, haloperidol, bromperidol, spiperone,reserpine, clocapramine hydrochloride, sulpiride, zotepine and the like.

(13) Antitumor Drug

6-O—(N-chloroacetylcarbamoyl)fumagillol, bleomycin, methotrexate,actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin,cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil,picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin,doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycinhydrochloride, peplomycin sulfate, vincristine sulfate, vinblastinesulfate, irinotecan hydrochloride, cyclophosphamide, melphalan,busulfan, thiotepa, procarbazine hydrochloride, cisplatin, azathioprine,mercaptopurine, tegafur, carmofur, cytarabine, methyltestosterone,testosterone propionate, testosterone enanthate, mepitiostane,fosfestrol, chlormadinone acetate, leuprorelin acetate, buserelinacetate and the like.

(14) Hypolipidemic Drug

clofibrate, ethyl2-chloro-3-[4-(2-methyl-2-phenylpropoxy)phenyl]propionate [Chemical andPharmaceutical Bulletin (Chem. Pharm. Bull), 38, 2792-2796 (1990)],pravastatin, simvastatin, probucol, bezafibrate, clinofibrate, nicomol,cholestyramine, dextran sulfate sodium and the like.

(15) Muscle Relaxant

pridinol, tubocurarine, pancuronium, tolperisone hydrochloride,chlorphenesin carbamate, baclofen, chlormezanone, mephenesin,chlorzoxazone, eperisone, tizanidine and the like.

(16) Antiepileptic Drug

phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione,carbamazepine, phenobarbital, primidone, sulthiame, sodium valproate,clonazepam, diazepam, nitrazepam and the like.

(17) Antidepressant

imipramine, clomipramine, noxiptiline, phenelzine, amitriptylinehydrochloride, nortriptyline hydrochloride, amoxapine, mianserinhydrochloride, maprotiline hydrochloride, sulpiride, fluvoxaminemaleate, trazodone hydrochloride and the like.

(18) Antiallergic Drug

diphenhydramine, chlorpheniramine, tripelennamine, metodilamine,clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglicate,tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine,mequitazine, azelastine hydrochloride, epinastine, ozagrelhydrochloride, pranlukast hydrate, seratrodast and the like.

(19) Cardiac Stimulants

trans-n-oxocamphor, terephyllol, aminophylline, etilefrine, dopamine,dobutamine, denopamine, aminophylline, vesnarinone, amrinone,pimobendan, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatosideC, G-strophanthin and the like.

(20) Vasodilator

oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan, clonidine,methyldopa, guanabenz and the like.

(21) Vasoconstrictor

dopamine, dobutamine denopamine and the like.

(22) Hypotensive Diuretic

hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine,diltiazem, nifedipine and the like.

(23) Therapeutic Drug for Diabetes

tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide,acarbose, epalrestat, troglitazone, glucagon, glymidine, glipizide,phenformin, buformin, metformin and the like.

(24) Antinarcotic

levallorphan, nalorphine, naloxone or a salt thereof and the like.

(25) Liposoluble Vitamins

(i) vitamin A: vitamin A₁, vitamin A₂ and retinol palmitate

(ii) vitamin D: vitamin D₁, D₂, D₃, D₄ and D₅

(iii) vitamin E: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol,dl-α-tocopherol nicotinate

(iv) vitamin K: vitamin K₁, K₂, K₃ and K₄

(v) folic acid (vitamin M) and the like.

(26) Vitamin Derivative

various derivatives of vitamins, for example, vitamin D₃ derivativessuch as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol,1-α-hydroxycholecalciferol, calcipotriol and the like, vitamin D,derivatives such as 5,6-trans-ergocalciferol and the like, and the like.

(27) Antiasthmatic

isoprenaline hydrochloride, salbutamol sulfate, procaterolhydrochloride, terbutaline sulfate, trimetoquinol hydrochloride,tulobuterol hydrochloride, orciprenaline sulfate, fenoterolhydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropiumbromide, flutropium bromide, theophylline, aminophylline, sodiumcromoglicate, tranilast, repirinast, amlexanox, ibudilast, ketotifen,terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride,pranlkast hydrate, seratrodast, dexamethasone, prednisolone,hydrocortisone, hydrocortisone sodium succinate, beclometasonedipropionate, ciclesonide and the like.

(28) Therapeutic Agent for Pollakisuria/Anischuria

flavoxate hydrochloride and the like.

(29) Therapeutic Agent for Atopic Dermatitis

sodium cromoglicate and the like.

(30) Therapeutic Agent for Allergic Rhinitis

sodium cromoglicate, chlorpheniramine maleate, alimemazine tartrate,clemastine fumarate, homochlorcyclizine hydrochloride, fexofenadine,mequitazine, ketotifen fumarate, cetirizine hydrochloride, oxatomide,azelastine, ebastine, epinastine hydrochloride, loratadine and the like.

(31) Hypertensor

dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin,lanatoside C, G-strophanthin and the like.

(32) Others

hydroxycam, diacerein, megestrol acetate, nicergoline, prostaglandinsand the like.

For combined use, the administration time of the compound of the presentinvention and the concomitant drug is not restricted, and the compoundof the present invention or the concomitant drug can be administered toan administration subject simultaneously, or may be administered atdifferent times. The dosage of the concomitant drug may be determinedaccording to the dose clinically used, and can be appropriately selecteddepending on an administration subject, administration route, disease,combination and the like.

The administration form of the combined use is not particularly limited,and the compound of the present invention and a concomitant drug onlyneed to be combined on administration. Examples of such administrationmode include the following:

(1) administration of a single preparation obtained by simultaneouslyprocessing the compound of the present invention and the concomitantdrug, (2) simultaneous administration of two kinds of preparations ofthe compound of the present invention and the concomitant drug, whichhave been separately produced, by the same administration route, (3)administration of two kinds of preparations of the compound of thepresent invention and the concomitant drug, which have been separatelyproduced, by the same administration route in a staggered manner, (4)simultaneous administration of two kinds of preparations of the compoundof the present invention and the concomitant drug, which have beenseparately produced, by different administration routes, (5)administration of two kinds of preparations of the compound of thepresent invention and the concomitant drug, which have been separatelyproduced, by different administration routes in a staggered manner(e.g., administration in the order of the compound of the presentinvention and the concomitant drug, or in the reverse order) and thelike.

The mixing ratio of the compound of the present invention and aconcomitant drug in the combination agent of the present invention canbe appropriately selected based on the subject of administration,administration route, disease and the like.

For example, while the content of the compound of the present inventionin the combination agent of the present invention varies depending onthe preparation form, it is generally about 0.01-100 wt %, preferablyabout 0.1-50 wt %, more preferably about 0.5-20 wt %, of the wholepreparation.

The content of the concomitant drug in the combination agent of thepresent invention varies depending on the preparation form, andgenerally about 0.01 to 100% by weight, preferably about 0.1 to 50% byweight, further preferably about 0.5 to 20% by weight, of the entirepreparation.

While the content of the additive such as a carrier and the like in thecombination agent of the present invention varies depending on the formof a preparation, it is generally about 1 to 99.99% by weight,preferably about 10 to 90% by weight, based on the preparation.

When the compound of the present invention and the concomitant drug areseparately prepared, the same content may be adopted.

The dose varies depending on the kind of the compound of the presentinvention, administration route, symptom, age of patients and the like.For example, for oral administration to patients (body weight about 60kg) with inflammatory bowel disease (IBD), about 0.1 mg/kg bodyweight—about 30 mg/kg body weight, preferably about 1 mg/kg bodyweight-20 mg/kg body weight, of compound (I), compound (I′) or compound(I″) can be administered once to several portions per day.

The dose of the medicament of the present invention as asustained-release preparation varies depending on the kind and contentof compound (I), compound (I′) or compound (I″), dosage form, period ofsustained drug release, subject animal of administration (e.g., mammalssuch as mouse, rat, hamster, guinea pig, rabbit, cat, dog, bovine,horse, swine, sheep, monkey, human and the like), and administrationobject. For example, for application by parenteral administration, about0.1 to about 100 mg of compound (I), compound (I′) or compound (I″)needs to be released from the administered preparation per 1 week.

Any amount of the concomitant drug can be adopted as long as the sideeffects do not cause a problem. The daily dosage in terms of theconcomitant drug varies depending on the severity, age, sex, bodyweight, sensitivity difference of the subject, administration period,interval, and nature, pharmacology, kind of the pharmaceuticalpreparation, kind of effective ingredient, and the like, and notparticularly restricted, and the amount of a drug is, in the case oforal administration for example, generally about 0.001 to 2000 mg,preferably about 0.01 to 500 mg, further preferably about 0.1 to 100 mg,per 1 kg of a mammal and this is generally administered once to 4-timesdivided in a day.

When the combination agent of the present invention is administered, thecompound of the present invention and the concomitant drug can beadministered simultaneously, or may be administered in a staggeredmanner. When administered at a time interval, the interval variesdepending on the effective ingredient, dosage form and administrationmethod, and, for example, when the concomitant drug is administeredfirst, a method in which the compound of the present invention isadministered within time range of from 1 minute to 3 days, preferablyfrom 10 minutes to 1 day, more preferably from 15 minutes to 1 hour,after administration of the concomitant drug is an example. When thecompound of the present invention is administered first, a method inwhich the concomitant drug is administered within time range of from 1minute to 1 day, preferably from 10 minutes to 6 hours, more preferablyfrom 15 minutes to 1 hour after administration of the compound of thepresent invention is an example.

EXAMPLES

The present invention is explained in more detail in the following byreferring to Examples, Formulation Examples and Experimental Examples,which are not to be construed as limitative and may be modified withoutdeparting from the scope of the invention.

Unless particularly specified, the elution in column chromatography inthe Examples was performed under observation by TLC (Thin LayerChromatography). For TLC observation, 60F254 manufactured by Merck wasused as a TLC plate, and the solvent used as an elution solvent forcolumn chromatography was used as a developing solvent. For detection, aUV detector was adopted. In silica gel column chromatography, NH meansuse of aminopropylsilane-bonded silica gel, and Diol means use of3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparativeHPLC (high performance liquid chromatography), C18 means use ofoctadecyl-bonded silica gel. The ratios of elution solvents are volumemixing ratios, unless otherwise specified. The room temperaturegenerally means a temperature about 10° C. to 35° C. For dryingextracts, sodium sulfate or magnesium sulfate was used.

In the chemical structure formulas described in Examples, the wavy linebonded to the asymmetric carbon

means one stereochemical structure which is not determined, and thesolid line

means a mixture of two stereochemical structure.

The abbreviations in the present specification or the Examples mean asfollows.

LC: liquid chromatography

MS: mass analysis spectrum

API: atmospheric pressure ionization method

M: molecular weight of the compound

NMR: nuclear magnetic resonance spectrum

Hz: hertz

J: coupling constant

m: multiplet

q: quartet

t: triplet

d: doublet

s: singlet

dt: double triplet

sxt: sextet

brs: broad singlet

ADDP: 1,1′-(azodicarbonyl)dipiperidine

BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

Boc: tert-butyloxycarbonyl group

Boc₂O: di-tert-butyl carbonate

CDI: carbonyldiimidazole

COMU:1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholino)]carbeniumhexafluorophosphate

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

DIEA: diisopropylethylamine

DMA: dimethylacetamide

DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

DPPA: diphenylphosphoryl azide

EtOH: ethanol

HATU: 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphorate

HMDS: 1,1,1,2,2,2-hexamethyldisilane

HOBt: 1H-benzo[d][1,2,3]triazol-1-ol hydrate

IPE: diisopropyl ether

MeOH: methanol

N: normal concentration

NaHMDS: sodium bis(trimethylsilyl)amide

n-BuLi: 1.6M n-butyllithium/hexane solution

NMP: N-methyl-2-pyrrolidone

Pd(PPh₃)₄: tetrakis(triphenylphosphine)palladium(0)

Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0)

t-: tert-

T3P: 1.6M2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide/ethylacetate solution or DMF solution

TEA: triethylamine

TFA: trifluoroacetic acid

THF: tetrahydrofuran

TMSCl: trimethylsilyl chloride, trimethylsilane chloride

WSC: N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride

XANTPHOS: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Example 1N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetamide

(Step 1)

To a solution of 1,3-difluoro-5-nitrobenzene (3 g, 18.86 mmol) in THE(60 mL) was added trimethylsilyl chloride (7.23 mL, 56.57 mmol) at −78°C. under nitrogen atmosphere. To the reaction solution was added sodiumhexamethyldisilazide (19.85 mL, 37.71 mmol), and the mixture was kept at−75° C. or lower. The reaction solution was stirred for 1 hr, and waterand ethyl acetate were added thereto. The organic layer was separated,and the aqueous layer was extracted with ethyl acetate. The organiclayer was dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent; hexane) to give(2,6-difluoro-4-nitrophenyl)trimethylsilane (3.51 g, 15.18 mmol, 80%) asa colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 0.42 (9H, s), 7.61-7.71 (2H, m).

(Step 2)

A solution of (2,6-difluoro-4-nitrophenyl)trimethylsilane (3.5 g, 15.13mmol) and 10% palladium on carbon (350 mg, 0.16 mmol, 50% wet) in MeOH(70 mL) was stirred at room temperature for 5 hr under hydrogenatmosphere (1 atm). The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent; ethylacetate/hexane) to give 3,5-difluoro-4-(trimethylsilyl)aniline (2.50 g,12.42 mmol, 82%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 0.30 (9H, s), 3.88 (2H, brs), 5.99-6.16 (2H,m).

(Step 3)

A solution of2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3g, 14.28 mmol), 2-oxoacetic acid hydrate (1.315 g, 14.28 mmol) anddiallylamine (1.779 mL, 14.28 mmol) in acetonitrile (20 mL) was stirredovernight at room temperature. The reaction mixture was concentratedunder reduced pressure, and the precipitate was washed with a mixedsolvent of ethyl acetate/hexane to give2-(diallylamino)-2-(3,6-dihydro-2H-pyran-4-yl)acetic acid (1.47 g, 6.19mmol, 43.4%) as a pale yellow solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.87-2.04 (1H, m), 2.07-2.23 (1H, m), 3.10(2H, dd, J=14.5, 7.0 Hz), 3.26 (2H, brs), 3.56-3.74 (2H, m), 3.84 (1H,brs), 4.06 (2H, brs), 5.01-5.29 (4H, m), 5.68 (1H, brs), 5.71-5.86 (2H,m).

(Step 4)

To a solution of 3,5-difluoro-4-(trimethylsilyl)aniline (0.933 g, 4.64mmol), 2-(diallylamino)-2-(3,6-dihydro-2H-pyran-4-yl)acetic acid (1.0 g,4.21 mmol), DMAP (0.566 g, 4.64 mmol) and DIEA (3.68 mL, 21.07 mmol) inethyl acetate (30 mL) was added T3P (3.72 mL, 6.32 mmol) at roomtemperature, and the mixture was stirred at 80° C. for 2 hr. To thereaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was dried over sodium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 3→70% ethyl acetate/hexane) to give2-(diallylamino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)acetamide(650 mg, 1.546 mmol, 36.7%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ0.34 (9H, t, J=1.3 Hz), 2.01-2.30 (2H, m),3.11 (2H, dd, J=4.5, 6.6 Hz), 3.31 (2H, dd, J=14.7, 5.7 Hz), 3.68-3.84(2H, m), 3.88 (1H, s), 4.22 (2H, q, J=2.6 Hz), 5.16-5.33 (4H, m),5.72-5.93 (3H, m), 6.99-7.13 (2H, m), 9.10 (1H, s).

(Step 5)

A solution of2-(diallylamino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)acetamide(650 mg, 1.55 mmol), Pd(PPh₃)₄ (53.6 mg, 0.05 mmol) and1,3-dimethylbarbituric acid (507 mg, 3.25 mmol) in THF (20 mL) wasstirred overnight at room temperature. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (solvent gradient; 3% ethylacetate/hexane→10% MeOH/ethyl acetate) to give2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)acetamide(540 mg, 1.586 mmol, 103%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.34 (9H, t, J=1.5 Hz), 1.73 (2H, brs),2.07-2.16 (1H, m), 2.18-2.39 (1H, m), 3.71-3.86 (2H, m), 4.02 (1H, s),4.11-4.25 (2H, m), 5.85 (1H, d, J=0.8 Hz), 7.01-7.16 (2H, m), 9.33 (1H,brs).

(Step 6)

A solution of2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)acetamide(540 mg, 1.59 mmol) and 10% palladium on carbon (300 mg, 2.82 mmol) inMeOH (20 mL) was stirred at room temperature for 2 days under hydrogenatmosphere (1 atm). The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (NH, solvent gradient;0→10% MeOH/ethyl acetate) to give2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide(525 mg, 1.533 mmol, 97%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.26-0.41 (9H, m), 1.34-1.45 (2H, m),1.46-1.68 (4H, m), 2.23-2.41 (1H, m), 3.28-3.54 (3H, m), 3.90-4.07 (2H,m), 7.05-7.18 (2H, m), 9.64 (1H, brs).

(Step 7)

A solution of2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide(40 mg, 0.12 mmol), HATU (48.9 mg, 0.13 mmol), DIEA (0.022 ML, 0.13mmol) and 2-(6-oxopyrimidin-1(6H)-yl)acetic acid (19.80 mg, 0.13 mmol)in DMF (4 mL) was stirred at room temperature for 1.5 hr. To thereaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0→8% MeOH/ethyl acetate) to give the title compound (36 mg,0.075 mmol, 64.4%) as white crystals.

MS(API): Calculated 478.6, Found 477.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ 0.31 (9H, t, J=0.9 Hz), 1.26-1.32 (1H, m),1.32-1.46 (2H, m), 1.61 (1H, d, J=12.5 Hz), 1.77-2.03 (1H, m), 3.18-3.31(2H, m), 3.86 (2H, t, J=10.6 Hz), 4.37 (1H, t, J=8.1 Hz), 4.58-4.82 (2H,m), 6.39 (1H, dd, J=6.8, 0.8 Hz), 7.25 (2H, d, J=9.8 Hz), 7.91 (1H, d,J=6.8 Hz), 8.37 (1H, s), 8.73 (1H, d, J=8.3 Hz), 10.59 (1H, s).

Example 2N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetamide

(Step 1)

To a solution of ethyl 2-(5-methyl-1,3,4-oxadiazol-2-yl)acetate (279 mg,1.64 mmol) in a mixed solvent of water (2 mL) and THF (1 mL) was addedlithium hydroxide monohydrate (68.9 mg, 1.64 mmol), and the mixture wasstirred at room temperature for 1 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was subjected toazeotropy with toluene to give lithium2-(5-methyl-1,3,4-oxadiazol-2-yl)acetate (250 mg, 1.689 mmol, 103%) as awhite solid.

¹H NMR (300 MHz, DMSO-d₆): δ 2.41 (3H, s), 3.35 (2H, s).

(Step 2)

A solution of2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide(48 mg, 0.14 mmol), HATU (58.6 mg, 0.15 mmol), DIEA (0.027 mL, 0.15mmol) and lithium 2-(5-methyl-1,3,4-oxadiazol-2-yl)acetate (22.83 mg,0.15 mmol) in DMF (4 mL) was stirred at room temperature for 1.5 hr. Tothe reaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0→10% MeOH/ethyl acetate) to give the title compound (40 mg,0.086 mmol, 61.2%) as white crystals.

MS(API): Calculated 466.6, Found 465.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ 0.31 (9H, t, J=1.3 Hz), 1.17-1.33 (1H, m),1.33-1.45 (2H, m), 1.50-1.69 (1H, m), 1.84-2.02 (1H, m), 2.46 (3H, s),3.19-3.30 (2H, m), 3.77-3.91 (2H, m), 3.94 (2H, d, J=2.6 Hz), 4.33 (1H,t, J=8.1 Hz), 7.25 (2H, d, J=9.8 Hz), 8.70 (1H, d, J=8.3 Hz), 10.61 (1H,s).

Example 3N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3-hydroxy-1,2-oxazole-5-carboxamide

A solution of2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide(100 mg, 0.29 mmol), COMU (138 mg, 0.32 mmol), DIEA (0.056 mL, 0.32mmol) and 3-hydroxy-1,2-oxazole-5-carboxylic acid (41.5 mg, 0.32 mmol)in DMF (2 mL) was stirred at room temperature for 2 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 0→10%MeOH/ethyl acetate) to giveN-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3-hydroxy-1,2-oxazole-5-carboxamide(107.5 mg, 0.237 mmol, 81%) as white crystals.

The obtained compound (107 mg) was subjected to optical resolution usingchiral column chromatography. The preparative fraction having a longerretention time was concentrated to give the title compound (46 mg, 99.4%ee) as a white solid.

MS(API): Calculated 453.5, Found 451.9 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ 0.20-0.39 (9H, m), 1.21-1.32 (1H, m),1.34-1.48 (2H, m), 1.68 (1H, d, J=11.3 Hz), 2.04-2.21 (1H, m), 3.16-3.29(2H, m), 3.73-3.95 (2H, m), 4.37 (1H, t, J=8.5 Hz), 6.73 (1H, s), 7.25(2H, d, J=9.8 Hz), 9.02 (1H, d, J=7.9 Hz), 10.68 (1H, s), 11.76 (1H,brs).

purification condition using chiral column chromatography

column: CHIRALPAK AD(ILAK001) 50 mmID×500 mmL

solvent: hexane/EtOH/acetic acid=70/30/0.1

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

Example 4N-(1-(4,4-difluorocyclohexyl)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-2-oxoethyl)-3-hydroxy-1,2-oxazole-5-carboxamide

(Step 1)

A solution of 1-chloro-2-fluoro-4-nitrobenzene (2.63 g, 15 mmol), HMDS(8.12 g, 55.50 mmol) and Pd(PPh₃)₄ (0.433 g, 0.38 mmol) in xylene (6.5mL) was stirred at 200° C. for 1 hr under microwave irradiation. To thereaction mixture was added ethyl acetate (about 150 mL), and theinsoluble substance was removed by filtration. The filtrate wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient; 2-5%ethyl acetate/hexane) to give (2-fluoro-4-nitrophenyl)trimethylsilane(3.22 g, 15.10 mmol, 101) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.36 (9H, d, J=1.1 Hz), 7.57 (1H, dd, J=8.1,5.5 Hz), 7.82 (1H, dd, J=8.1, 2.1 Hz), 7.99 (1H, dd, J=8.1, 2.1 Hz).

(Step 2)

A solution of (2-fluoro-4-nitrophenyl)trimethylsilane (3.22 g, 15.10mmol) and 10% palladium-carbon (1.0 g, 0.47 mmol) in MeOH (65 mL) wasstirred at room temperature for 3.5 hr under hydrogen atmosphere (1atm). The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 2→15% MeOH/ethylacetate) to give 3-fluoro-4-(trimethylsilyl)aniline (1.89 g, 10.31 mmol,68.3%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.26 (9H, d, J=0.8 Hz), 3.79 (2H, brs), 6.31(1H, dd, J=10.6, 2.3 Hz), 6.44 (1H, dd, J=7.9, 1.9 Hz), 7.13 (1H, dd,J=7.9, 6.8 Hz).

(Step 3)

To a solution of methyl2-(((benzyloxy)carbonyl)amino)-2-(dimethoxyphosphoryl)acetate (2.470 g,7.46 mmol) in acetonitrile (25 mL) was added DBU (1.113 mL, 7.46 mmol)at room temperature, and the mixture was stirred for 30 min. To thereaction mixture was added a solution of 4,4-difluorocyclohexanone (1 g,7.46 mmol) in acetonitrile (5 mL) at room temperature, and the mixturewas stirred overnight. To the reaction mixture were added water andethyl acetate, and the organic layer was separated. The organic layerwas dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was crystallized from ethylacetate/hexane to give methyl2-(((benzyloxy)carbonyl)amino)-2-(4,4-difluorocyclohexylidene)acetate(2.13 g, 6.28 mmol, 84%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃): δ1.88-2.17 (4H, m), 2.32-2.57 (2H, m), 2.92(2H, d, J=6.4 Hz), 3.68-3.86 (3H, m), 5.14 (2H, s), 6.04 (1H, brs),7.30-7.47 (5H, m).

(Step 4)

To a solution of methyl2-(((benzyloxy)carbonyl)amino)-2-(4,4-difluorocyclohexylidene)acetate (1g, 2.95 mmol) in a mixed solvent of THE (10 mL) and MeOH (10.00 mL) wasadded 1N aqueous sodium hydroxide solution (4.42 mL, 4.42 mmol) at roomtemperature, and the mixture was stirred overnight. The reaction mixturewas concentrated under reduced pressure. To the obtained residue wereadded water and 1N hydrochloric acid. The precipitate was collected byfiltration, and washed with water and hexane to give2-(((benzyloxy)carbonyl)amino)-2-(4,4-difluorocyclohexylidene)aceticacid (790 mg, 2.428 mmol, 82%) as a pale yellow solid.

¹H NMR (300 MHz, DMSO-d₆): δ 1.67-2.12 (4H, m), 2.27-2.41 (2H, m),2.60-2.80 (2H, m), 5.06 (2H, s), 7.07-7.54 (5H, m), 8.94 (1H, s), 12.69(1H, brs).

(Step 5)

To a solution of 3-fluoro-4-(trimethylsilyl)aniline (225 mg, 1.23 mmol),2-(((benzyloxy)carbonyl)amino)-2-(4,4-difluorocyclohexylidene)aceticacid (400 mg, 1.23 mmol), DIEA (1.074 mL, 6.15 mmol) and DMAP (165 mg,1.35 mmol) in ethyl acetate (25 mL) was added T3P (0.723 mL, 1.23 mmol)at room temperature, and the mixture was stirred at 70° C. for 2 hr. Tothe reaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was dried over sodium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 3→50% ethyl acetate/hexane) to give a mixture (420 mg) ofbenzyl(1-(4,4-difluorocyclohexylidene)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-2-oxoethyl)carbamateand benzyl(1-(4,4-difluorocyclohex-1-en-1-yl)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-2-oxoethyl)carbamate.The mixture was directly used in the next step.

(Step 6)

To a solution of a mixture (420 mg) of benzyl(1-(4,4-difluorocyclohexylidene)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-2-oxoethyl)carbamateand benzyl(1-(4,4-difluorocyclohex-1-en-1-yl)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-2-oxoethyl)carbamatein MeOH (25 mL) was added 10% palladium-carbon (91 mg, 0.043 mmol, 50%wet). The mixture was stirred at room temperature for 5 hr underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (NH, solventgradient; 50→100% ethyl acetate/hexane) to give2-amino-2-(4,4-difluorocyclohexyl)-N-(3-fluoro-4-(trimethylsilyl)phenyl)acetamide(278 mg, 0.776 mmol, 91%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.26-0.32 (9H, m), 1.36-1.49 (1H, m),1.59-1.96 (5H, m), 2.05-2.30 (3H, m), 3.46 (1H, d, J=3.4 Hz), 7.20 (1H,dd, J=7.9, 1.9 Hz), 7.28-7.36 (1H, m), 7.48 (1H, dd, J=10.4, 1.7 Hz),9.60 (1H, brs). (NH₂ proton was not observed.)

(Step 7)

A solution of2-amino-2-(4,4-difluorocyclohexyl)-N-(3-fluoro-4-(trimethylsilyl)phenyl)acetamide(40 mg, 0.11 mmol), DIEA (0.021 mL, 0.12 mmol),3-hydroxy-1,2-oxazole-5-carboxylic acid (15.84 mg, 0.12 mmol) and COMU(52.6 mg, 0.12 mmol) in DMF (2 mL) was stirred overnight at roomtemperature. To the reaction mixture were added water and ethyl acetate,and the organic layer was separated. The organic layer was dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30-100% ethyl acetate/hexane) to givethe title compound (23 mg, 0.049 mmol, 43.9%) as white crystals.

MS(API): Calculated 469.5, Found 468.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.16-0.35 (9H, m), 1.19-1.51 (2H, m),1.55-1.94 (4H, m), 1.94-2.14 (3H, m), 4.45 (1H, t, J=8.3 Hz), 6.73 (1H,s), 7.25-7.44 (2H, m), 7.53 (1H, d, J=9.8 Hz), 9.02 (1H, d, J=8.3 Hz),10.51 (1H, s), 11.74 (1H, brs).

Example 5(3S)—N-(1-(4,4-difluorocyclohexyl)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide(Mixture of Two Diastereomers)

(Step 1)

A solution of (S)-1-(4-methoxyphenyl)ethanamine (30 g, 198.41 mmol) and2-methylenesuccinic acid (25.8 g, 198.41 mmol) in NMP (150 mL) wasstirred at 130° C. for 4 hr. To the reaction mixture was added water(400 mL), the mixture was cooled, and the precipitate was collected byfiltration to give1-((S)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylic acid(46.7 g, 177 mmol, 89%) as a white solid.

(Step 2)

A solution of1-((S)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylic acid(38.5 g, 146.23 mmol), benzyl bromide (19.13 mL, 160.85 mmol) and cesiumcarbonate (52.4 g, 160.85 mmol) in DMF (160 mL) was stirred at roomtemperature for 45 min. To the reaction mixture were added water andethyl acetate, and the organic layer was separated. The organic layerwas dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 45→100% ethyl acetate/hexane) to givebenzyl(S)-1-((S)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylate(22.7 g, 64.2 mmol, 44%) and benzyl(R)-1-((S)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylate(20.46 g, 57.9 mmol, 40%).

Benzyl(S)-1-((S)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylate

¹H NMR (300 MHz, CDCl₃): δ1.47 (3H, d, J=7.2 Hz), 2.59-2.83 (2H, m),3.03-3.23 (2H, m), 3.47-3.57 (1H, m), 3.79 (3H, s), 5.14 (2H, s), 5.44(1H, q, J=7.1 Hz), 6.82-6.89 (2H, m), 7.17-7.24 (2H, m), 7.29-7.43 (5H,m).

Benzyl(R)-1-((S)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylate

¹H NMR (300 MHz, CDCl₃): δ1.49 (3H, d, J=7.2 Hz), 2.59-2.82 (2H, m),3.11-3.30 (2H, m), 3.45-3.58 (1H, m), 3.79 (3H, s), 5.07 (2H, d, J=0.8Hz), 5.44 (1H, q, J=6.9 Hz), 6.80-6.87 (2H, m), 7.15-7.22 (2H, m),7.22-7.29 (2H, m), 7.30-7.39 (3H, m).

(Step 3)

A solution of benzyl(S)-1-((S)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylate(22.7 g, 64.23 mmol) and 10% palladium-carbon (2 g, 0.94 mmol, 50% wet)in ethyl acetate (100 mL) was stirred at room temperature for 2 hr underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure to give(S)-1-((S)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylic acid(14.4 g, 54.7 mmol, 85%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ1.51 (3H, d, J=7.2 Hz), 2.65-2.85 (2H, m),3.06-3.16 (1H, m), 3.16-3.26 (1H, m), 3.57 (1H, dd, J=9.4, 5.7 Hz), 3.80(3H, s), 5.45 (1H, q, J=7.2 Hz), 6.87 (2H, d, J=8.7 Hz), 7.19-7.25 (2H,m).

(Step 4)

A solution of(S)-1-((S)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylic acid(14.4 g, 54.69 mmol) in TFA (80 mL) was stirred at 80° C. for 4 hr. TFAwas removed by subjecting the mixture to azeotropy with toluene to give(S)-5-oxopyrrolidine-3-carboxylic acid (6.78 g, 52.5 mmol, 96%) as awhite solid.

¹H NMR (300 MHz, DMSO-d₆): δ2.22-2.42 (2H, m), 3.15-3.37 (2H, m),3.37-3.50 (1H, m), 7.62 (1H, brs), 12.55 (1H, s).

(Step 5)

A solution of2-amino-2-(4,4-difluorocyclohexyl)-N-(3-fluoro-4-(trimethylsilyl)phenyl)acetamide(40 mg, 0.11 mmol), COMU (52.6 mg, 0.12 mmol), DIEA (0.021 mL, 0.12mmol) and (S)-5-oxopyrrolidine-3-carboxylic acid (15.85 mg, 0.12 mmol)in DMF (2 mL) was stirred overnight at room temperature. The precipitatewas collected by filtration, and purified by silica gel columnchromatography (solvent gradient; 30% ethyl acetate/hexane-15%MeOH/ethyl acetate) to give the title compound (26 mg, 0.055 mmol,49.6%) as a white powder.

MS(API): Calculated 469.6, Found 468.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.16-0.35 (9H, m), 1.25-1.47 (2H, m, J=6.0Hz), 1.53-1.90 (5H, m), 1.94-2.11 (2H, m), 2.20-2.34 (2H, m), 3.06-3.54(3H, m), 4.24-4.49 (1H, m), 7.24-7.41 (2H, m), 7.45-7.60 (2H, m),8.25-8.44 (1H, m), 10.44 (1H, s).

Example 6N-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

(Step 1)

To 0.5M (4-(bis(trimethylsilyl)amino)phenyl)magnesium chloride THEsolution (100 mL, 50.00 mmol) was added TMSCl (7.03 mL, 55.00 mmol) atroom temperature, and the mixture was stirred for 30 min. To thereaction solution was added 0.1N hydrochloric acid under ice-cooling,the mixture was stirred for 10 min, and saturated aqueous sodiumhydrogencarbonate solution and ethyl acetate were added thereto. Theorganic layer was separated, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 5-30%ethyl acetate/hexane) to give 4-(trimethylsilyl)aniline (6.51 g, 39.4mmol, 79%) as a yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ0.09-0.19 (9H, m), 5.14 (2H, s), 6.49-6.60(2H, m), 7.09-7.19 (2H, m).

(Step 2)

A solution of2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.5 g, 7.14 mmol), glyoxylic acid monohydrate (0.657 g, 7.14 mmol) andN-methylbenzylamine (0.917 mL, 7.14 mmol) in acetonitrile (15 mL) wasstirred overnight at room temperature. The reaction solution wasconcentrated under reduced pressure to give 2-(benzyl(methyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)acetic acid (810.2 mg, 3.10mmol, 43.4%) as a pale yellow solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.90-2.32 (5H, m), 3.60 (2H, s), 3.63-3.73(3H, m), 4.00-4.14 (2H, m), 5.79 (1H, brs), 7.10-7.50 (5H, m).

(Step 3)

To a solution of2-(benzyl(methyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)acetic acid (800mg, 3.06 mmol), DIEA (2.423 mL, 13.91 mmol),3,5-difluoro-4-(trimethylsilyl)aniline (560 mg, 2.78 mmol) and DMAP (357mg, 2.92 mmol) in ethyl acetate (20 mL) was added T3P (2.61 mL, 4.17mmol) at room temperature, and the mixture was stirred at 80° C. for 5hr. To the reaction mixture were added water and ethyl acetate, and theorganic layer was separated. The organic layer was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 0→20% ethyl acetate/hexane) to give2-(benzyl(methyl)amino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)acetamide(1.00 g, 2.249 mmol, 81%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.34 (9H, t, J=1.3 Hz), 2.17 (2H, s), 2.22(3H, s), 3.48-3.66 (3H, m), 3.69-3.88 (2H, m), 4.18-4.26 (2H, m), 5.91(1H, s), 7.03-7.12 (2H, m), 7.28-7.43 (5H, m), 9.09 (1H, s).

(Step 4)

A solution of2-(benzyl(methyl)amino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)acetamide(1.0 g, 2.25 mmol) and 10% palladium-carbon (100 mg, 0.047 mmol, 50%wet) in MeOH (20 mL) was stirred at room temperature for 5 hr underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (NH, solvent;ethyl acetate/hexane) to giveN-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(methylamino)-2-(tetrahydro-2H-pyran-4-yl)acetamide(759.5 mg, 2.131 mmol, 95%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.34 (9H, t, J=1.3 Hz), 1.35-1.54 (3H, m),1.59-1.65 (1H, m), 2.00-2.13 (1H, m), 2.17 (1H, s), 2.46 (3H, s), 2.92(1H, d, J=4.9 Hz), 3.27-3.45 (2H, m), 3.87-4.09 (2H, m), 7.06-7.20 (2H,m), 9.40 (1H, brs).

(Step 5)

To a solution ofN-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(methylamino)-2-(tetrahydro-2H-pyran-4-yl)acetamide(755 mg, 2.12 mmol), DIEA (0.724 mL, 4.24 mmol) and3-hydroxy-1,2-oxazole-5-carboxylic acid (328 mg, 2.54 mmol) in DMF (15mL) was added COMU (1088 mg, 2.54 mmol) at 0° C., and the mixture wasstirred at room temperature for 5 hr. To the reaction mixture were addedwater and ethyl acetate, and the organic layer was separated. Theorganic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0-50% ethylacetate/hexane) to give the title compound (740.7 mg, 1.584 mmol, 74.8%)as a colorless amorphous solid.

MS(API): Calculated 467.5, Found 466.0 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.31 (9H, s), 1.09-1.62 (4H, m), 2.16-2.37(1H, m), 3.06-3.22 (3H, m), 3.26-3.43 (2H, m), 3.77-3.93 (2H, m), 4.88(1H, d, J=10.6 Hz), 6.36-6.63 (1H, m), 7.19-7.36 (2H, m), 10.27-10.82(1H, m), 11.72 (1H, s).

Example 7(3S)—N-((1R)-2-((4-tert-butyl-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

(Step 1)

A solution of2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4,4-difluorocyclohexyl)acetamide(1.11 g, 3.24 mmol), Boc₂O (0.849 g, 3.89 mmol) and TEA (0.683 mL, 4.86mmol) in THF (10 mL) was stirred overnight at room temperature. To thereaction mixture were added aqueous sodium hydrogencarbonate solutionand ethyl acetate, and the organic layer was separated. The organiclayer was dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 1→30% ethyl acetate/hexane) togive tert-butyl(2-((4-(tert-butyl)-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate(1.35 g, 3.05 mmol, 94%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ1.35 (9H, s), 1.38-1.53 (11H, m), 1.61-2.02(5H, m), 2.06-2.23 (2H, m, J=4.2 Hz), 4.05 (1H, d, J=8.7 Hz), 5.15 (1H,d, J=8.3 Hz), 7.05 (1H, dd, J=8.3, 2.3 Hz), 7.16-7.24 (1H, m), 7.39 (1H,dd, J=14.0, 2.3 Hz), 8.12 (1H, brs).

(Step 2)

tert-Butyl(2-((4-(tert-butyl)-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate(1.35 g) was subjected to optical resolution using chiral columnchromatography. The preparative fraction having a shorter retention timewas concentrated to give tert-butyl((1S)-2-((4-(tert-butyl)-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate(shorter retention time) (601 mg, >99.9% ee). The preparative fractionhaving a longer retention time was concentrated to give tert-butyl((1R)-2-((4-(tert-butyl)-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate(longer retention time) (553 mg, >99.9% ee).

purification condition using chiral column chromatography

column: CHIRALPAK AD(JG001)50 mmID×500 mmL

solvent: hexane/2-propanol=700/300

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

To a solution of tert-butyl((1R)-2-((4-(tert-butyl)-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate(553 mg, 1.25 mmol) in ethyl acetate (4 mL) was added 4M hydrogenchloride/ethyl acetate (5 mL), and the mixture was stirred at roomtemperature for 2 days. The reaction mixture was concentrated underreduced pressure, and the precipitate was washed with a mixed solvent ofethyl acetate/hexane to give(2R)-2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4,4-difluorocyclohexyl)acetamidehydrochloride (461 mg, 1.217 mmol, 97%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.27-1.38 (10H, m), 1.40-1.57 (1H, m),1.62-1.77 (2H, m), 1.79-1.91 (2H, m), 1.94-2.13 (3H, m), 3.85 (1H, d,J=6.4 Hz), 7.20-7.38 (2H, m), 7.52 (1H, dd, J=14.9, 1.7 Hz), 8.35 (3H,brs), 10.81 (1H, s).

(Step 4)

A solution of(2R)-2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4,4-difluorocyclohexyl)acetamidehydrochloride (60 mg, 0.16 mmol), DIEA (45.0 mg, 0.35 mmol),(S)-5-oxopyrrolidine-3-carboxylic acid (24.54 mg, 0.19 mmol) and HATU(72.3 mg, 0.19 mmol) in DMF (2 mL) was stirred at room temperature for 2hr. To the reaction mixture was added water, and the precipitate wascollected by filtration, and washed with water to give the titlecompound (16.00 mg, 0.035 mmol, 22.28%) as a white solid.

MS(API): Calculated 453.5, Found 452.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ1.19-1.43 (11H, m), 1.54-1.64 (1H, m),1.68-1.88 (4H, m), 1.93-2.09 (2H, m), 2.27 (2H, d, J=8.5 Hz), 3.18 (1H,dd, J=9.1, 6.1 Hz), 3.26-3.37 (1H, m), 3.38-3.51 (1H, m), 4.40 (1H, t,J=8.3 Hz), 7.17-7.32 (2H, m), 7.46-7.60 (2H, m), 8.37 (1H, d, J=8.5 Hz),10.34 (1H, s).

Example 8N-((1R)-2-((4-tert-butyl-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-2-oxo-1,3-oxazolidine-5-carboxamide(mixture of two diastereomers)

A solution of(2R)-2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4,4-difluorocyclohexyl)acetamidehydrochloride (41 mg, 0.11 mmol), DIEA (0.040 mL, 0.23 mmol),2-oxooxazolidine-5-carboxylic acid (15.60 mg, 0.12 mmol) and HATU (45.3mg, 0.12 mmol) in DMF (2 mL) was stirred at room temperature for 2 hr.To the reaction mixture was added water, and the precipitate wascollected by filtration, and washed with water to give the titlecompound (44 mg, 0.097 mmol, 891) as a white solid.

MS(API): Calculated 455.5, Found 454.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ1.15-1.44 (11H, m), 1.56-1.94 (5H, m), 2.06(2H, brs), 3.23-3.43 (1H, m), 3.70 (1H, t, J=9.1 Hz), 4.27-4.52 (1H, m),5.05 (1H, dt, J=9.3, 5.9 Hz), 7.10-7.35 (2H, m), 7.52 (1H, d, J=15.1Hz), 7.71 (1H, s), 8.35-8.54 (1H, m), 10.39 (1H, d, J=6.8 Hz).

Example 9N-((1R)-2-((4-tert-butyl-3-chlorophenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3,3,3-trifluoropropanamide

(Step 1)

To a solution of methyl2-(((benzyloxy)carbonyl)amino)-2-(dimethoxyphosphoryl)acetate (10 g,30.19 mmol) in acetonitrile (50 mL) was added DBU (4.51 mL, 30.19 mmol)at room temperature, and the mixture was stirred for 30 min. Then, asolution of dihydro-2H-pyran-4(3H)-one (3.02 g, 30.19 mmol) inacetonitrile (5 mL) was added thereto, and the mixture was stirredovernight at room temperature. To the reaction mixture were added waterand ethyl acetate, and the organic layer was separated. The organiclayer was washed with saturated brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure to give methyl2-(((benzyloxy)carbonyl)amino)-2-(dihydro-2H-pyran-4(3H)-ylidene)acetate(9.17 g, 30.0 mmol, 99%) as a pale yellow oil. ¹H NMR (300 MHz, CDCl₃):δ2.37-2.55 (2H, m), 2.93 (2H, t, J=4.9 Hz), 3.67-4.02 (7H, m), 5.14 (2H,s), 5.98 (1H, brs), 7.32-7.41 (5H, m).

(Step 2)

A solution of methyl2-(((benzyloxy)carbonyl)amino)-2-(dihydro-2H-pyran-4(3H)-ylidene)acetate(9.17 g, 30.03 mmol) and 10% palladium-carbon (0.1 g, 0.047 mmol, 50%wet) in MeOH (200 mL) was stirred at room temperature for 2 days underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure to give methyl2-amino-2-(tetrahydro-2H-pyran-4-yl)acetate as an orange oil. Thiscompound was used in the next step without purification.

(Step 3)

To a solution of methyl 2-amino-2-(tetrahydro-2H-pyran-4-yl)acetate(5.28 g, 30.48 mmol) in THF (100 mL) were added a solution of Boc₂O(8.40 mL, 36.58 mmol) in THF (50 mL) and TEA (6.37 mL, 45.72 mmol), andthe mixture was stirred at room temperature for 5 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 5→100%ethyl acetate/hexane) to give methyl2-((tert-butoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetate (4.77g, 17.45 mmol, 57.3%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃):δ1.41-1.55 (13H, m), 1.92-2.03 (1H, m), 3.25-3.43 (2H, m), 3.73 (3H,brs), 3.91-4.04 (2H, m), 4.28 (1H, dd, J=8.9, 5.5 Hz), 5.08 (1H, d,J=9.1 Hz).

(Step 4)

To a solution of methyl2-((tert-butoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetate (4.77g, 17.45 mmol) in a mixed solvent of THF (10 mL) and water (4 mL) wasadded lithium hydroxide monohydrate (1.099 g, 26.18 mmol), and themixture was stirred overnight at room temperature. THF was evaporatedunder reduced pressure, 1N hydrochloric acid was added thereto, and themixture was extracted with ethyl acetate. The organic layer was driedover magnesium sulfate, and the solvent was evaporated under reducedpressure to give2-((tert-butoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(3.07 g, 11.84 mmol, 67.8-) as a white solid. ¹H NMR (300 MHz, CDCl₃):δ1.45 (9H, s), 1.48-1.68 (4H, m), 1.92-2.21 (1H, m), 3.27-3.50 (2H, m),4.02 (2H, d, J=11.0 Hz), 4.29 (1H, brs), 5.14 (1H, d, J=8.3 Hz).

(COOH group D hydrogen was not observed.)

(Step 5)

Sulfuric acid (600 g, 6117.55 mmol) was cooled to 0° C. or lower, and2-(tert-butyl)aniline (75.24 g, 504.18 mmol) was slowly added theretowhile the mixture was kept at 10° C. or lower. The mixture was stirredat 0° C. for 40 min, and potassium nitrate (61.2 g, 605.01 mmol) wasslowly added thereto while the mixture was kept at 5° C. or lower. Themixture was stirred at 0° C. for 30 min, the reaction mixture was pouredinto ice water (3000 mL), and the mixture was extracted with ethylacetate/THF (3:1, v/v) (×3). The organic layer was separated, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure to give 2-(tert-butyl)-5-nitroaniline (78.95 g, 406 mmol, 81%)as a yellow solid. ¹H NMR (300 MHz, CDCl₃): δ1.44 (9H, s), 4.12 (2H,brs), 7.34 (1H, d, J=8.7 Hz), 7.46 (1H, d, J=2.3 Hz), 7.54 (1H, dd).

(Step 6)

2-(tert-Butyl)-5-nitroaniline (8.95 g, 46.08 mmol) was suspended inconc. hydrochloric acid (50 mL) at 0° C., and a solution of sodiumnitrite (3.50 g, 50.69 mmol) in water (20 mL) was slowly added theretowhile the mixture was kept at 0-5° C. The reaction mixture was added toa solution of copper(I) chloride (5.02 g, 50.69 mmol) in conc.hydrochloric acid (50 mL) at 0° C., and the mixture was vigorouslystirred. The reaction mixture was stirred at 70° C. for 30 min, andpoured into water (500 mL). The mixture was extracted with ethylacetate, the organic layer was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure to give1-(tert-butyl)-2-chloro-4-nitrobenzene (8.57 g, 40.1 mmol, 87%) as ayellow powder.

¹H NMR (300 MHz, CDCl₃): δ1.52 (9H, s), 7.60 (1H, d, J=8.7 Hz), 8.04(1H, dd, J=8.9, 2.5 Hz), 8.22 (1H, d, J=2.3 Hz).

(Step 7)

To a solution of 1-(tert-butyl)-2-chloro-4-nitrobenzene (8.57 g, 40.11mmol) and nickel(II) bromide (0.438 g, 2.01 mmol) in a mixed solvent ofMeOH (170 mL) and THF (170 mL) was added sodium borohydride (4.55 g,120.33 mmol) at 0° C., and the mixture was stirred at 0° C. for 20 min,and then at room temperature for 40 min. To the reaction mixture wasadded aqueous sodium hydrogencarbonate solution, and the mixture wasextracted with ethyl acetate (×3). The organic layer was dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 4-20% ethyl acetate/hexane) to give4-(tert-butyl)-3-chloroaniline (7.30 g, 39.7 mmol, 995) as a colorlessoil.

¹H NMR (300 MHz, CDCl₃): δ1.43 (9H, s), 3.58 (2H, brs), 6.51 (1H, dd,J=8.7, 2.6 Hz), 6.71 (1H, d, J=2.6 Hz), 7.18 (1H, d, J=8.7 Hz).

(Step 8)

To a solution of2-((tert-butoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid(1.55 g, 5.98 mmol), 4-(tert-butyl)-3-chloroaniline (1.098 g, 5.98mmol), DMAP (0.803 g, 6.58 mmol) and DIEA (5.22 mL, 29.89 mmol) in ethylacetate (20 mL) was added T3P (5.27 mL, 8.97 mmol) at room temperature.The reaction mixture was stirred overnight at 60° C., water and ethylacetate were added thereto, and the organic layer was separated. Theorganic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure to give tert-butyl(2-((4-(tert-butyl)-3-chlorophenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(2.23 g, 5.25 mmol, 88%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ1.41-1.51 (19H, m), 1.59-1.72 (2H, m),2.08-2.25 (1H, m), 3.39 (2H, t, J=11.7 Hz), 3.90-4.07 (3H, m), 5.07 (1H,d, J=7.9 Hz), 7.29-7.41 (3H, m), 7.56-7.63 (1H, m), 7.95 (1H, brs).

(Step 9)

tert-Butyl((1R)-2-((4-(tert-butyl)-3-chlorophenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(2.23 g) was subjected to optical resolution using chiral columnchromatography. The preparative fraction having a longer retention timewas concentrated to give tert-butyl((1R)-2-((4-(tert-butyl)-3-chlorophenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(longer retention time) (1.0 g, >99.9% ee) as a white solid.

purification condition using chiral column chromatography

column: CHIRALPAK IA(QK001)50 mmID×500 mmL

solvent: hexane/EtOH=800/200

flow rate: 60 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 10)

To a solution of tert-butyl((1R)-2-((4-(tert-butyl)-3-chlorophenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate(1.0 g, 2.35 mmol) in ethyl acetate (10 mL) was added 4M hydrogenchloride/ethyl acetate (5 mL), and the mixture was stirred overnight atroom temperature. The precipitate was washed with ethyl acetate/hexaneto give(2R)-2-amino-N-(4-(tert-butyl)-3-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)acetamidehydrochloride (770 mg, 2.131 mmol, 91%) as a white solid.

(Step 11)

A solution of(2R)-2-amino-N-(4-(tert-butyl)-3-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)acetamidehydrochloride (50 mg, 0.14 mmol), DIEA (0.058 mL, 0.33 mmol),3,3,3-trifluoropropanoic acid (0.013 mL, 0.15 mmol) and HATU (57.9 mg,0.15 mmol) in DMF (2 mL) was stirred overnight at room temperature. Tothe reaction mixture was added water, and the precipitate was collectedby filtration, and washed with water to give the title compound (60.0mg, 0.138 mmol, 100%) as a white solid.

MS(API): Calculated 434.9, Found 433.0 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ1.14-1.46 (12H, m), 1.56 (1H, d, J=12.1 Hz),1.82-2.01 (1H, m), 3.17-3.28 (2H, m), 3.34-3.51 (2H, m), 3.77-3.93 (2H,m), 4.38 (1H, t, J=8.3 Hz), 7.41 (2H, s), 7.77 (1H, s), 8.59 (1H, d,J=8.7 Hz), 10.37 (1H, s).

Example 10N-((1R)-2-((4-tert-butyl-3-chlorophenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3,3,3-trifluoro-2-hydroxypropanamide(Single Optical Isomer, Shorter Retention Time) Example 11N-((1R)-2-((4-tert-butyl-3-chlorophenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3,3,3-trifluoro-2-hydroxypropanamide(Single Optical Isomer, Longer Retention Time)

A solution of(2R)-2-amino-N-(4-(tert-butyl)-3-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)acetamidehydrochloride obtained in Step 10 of Example 9 (52 mg, 0.14 mmol), DIEA(0.060 mL, 0.35 mmol), 3,3,3-trifluoro-2-hydroxypropanoic acid (0.016mL, 0.16 mmol) and HATU (60.2 mg, 0.16 mmol) in DMF (2 mL) was stirredovernight at room temperature. To the reaction mixture was added water,and the mixture was extracted with ethyl acetate. The organic layer wasdried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30→70% ethyl acetate/hexane) to givethe title compound (17 mg, 0.038 mmol, 26.2%) of Example 10 from thepreparative fraction having a shorter retention time, and the titlecompound (15 mg, 0.033 mmol, 23.1%) of Example 11 from the preparativefraction having a longer retention time.

The title compound of Example 10

MS(API): Calculated 450.9, Found 448.9 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ1.15-1.45 (12H, m), 1.47-1.58 (1H, m),1.86-2.07 (1H, m), 3.14-3.27 (2H, m), 3.76-3.91 (2H, m), 4.43 (1H, t,J=8.1 Hz), 4.67 (1H, t, J=7.6 Hz), 7.33 (1H, d, J=6.8 Hz), 7.41 (2H, s),7.76 (1H, s), 8.12 (1H, d, J=9.1 Hz), 10.41 (1H, s).

The title compound of Example 11

MS(API): Calculated 450.9, Found 448.9 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ1.15-1.46 (12H, m), 1.55 (1H, d, J=12.5 Hz),1.82-2.09 (1H, m), 3.17-3.26 (2H, m), 3.78-3.94 (2H, m), 4.40 (1H, t,J=8.3 Hz), 4.71 (1H, t, J=7.9 Hz), 7.06 (1H, d, J=7.2 Hz), 7.41 (2H, s),7.76 (1H, s), 8.34 (1H, d, J=9.8 Hz), 10.40 (1H, s).

Example 123-hydroxy-N-(1-(4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl)amino)ethyl)-N-methyl-1,2-oxazole-5-carboxamide

(Step 1)

A solution of (4-methoxyphenyl)boronic acid (9.42 g, 62.01 mmol),glyoxylic acid monohydrate (5.71 g, 62.01 mmol) and N-methylallylamine(5.95 mL, 62.01 mmol) in acetonitrile (120 mL) was stirred at 60° C. for2.5 hr. To the reaction mixture was added ethyl acetate, and theprecipitate was removed by filtration. The filtrate was concentratedunder reduced pressure, and the obtained residue was purified by silicagel column chromatography (Diol, solvent gradient; 0→20% MeOH/ethylacetate) to give 2-(allyl(methyl)amino)-2-(4-methoxyphenyl)acetic acid(4.91 g, 20.87 mmol, 33.71) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ2.20 (3H, s), 3.03-3.21 (2H, m), 3.75 (3H,s), 4.11 (1H, s), 5.14-5.28 (2H, m), 5.73-5.92 (1H, m), 6.87-6.97 (2H,m), 7.26-7.37 (2H, m).

(Step 2)

A solution of 2-(allyl(methyl)amino)-2-(4-methoxyphenyl)acetic acid (2.8g, 11.90 mmol), 4-(trimethylsilyl)aniline (2.066 g, 12.50 mmol), DIEA(4.16 mL, 23.80 mmol) and HATU (5.43 g, 14.28 mmol) in DMF (50 mL) wasstirred overnight at room temperature. To the reaction mixture wereadded water and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with water, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0→30% ethyl acetate/hexane) to give2-(allyl(methyl)amino)-2-(4-methoxyphenyl)-N-(4-(trimethylsilyl)phenyl)acetamide(2.82 g, 7.37 mmol, 61.9%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ0.25 (9H, s), 2.20 (3H, s), 2.95-3.14 (2H, m),3.79 (3H, s), 4.10 (1H, s), 5.15-5.30 (2H, m), 5.78-5.98 (1H, m),6.81-6.94 (2H, m), 7.18-7.31 (2H, m), 7.44-7.52 (2H, m), 7.54-7.62 (2H,m), 9.25 (1H, s).

(Step 3)

To a solution of2-(allyl(methyl)amino)-2-(4-methoxyphenyl)-N-(4-(trimethylsilyl)phenyl)acetamide(2.82 g, 7.37 mmol) and 1,3-dimethylbarbituric acid (1.266 g, 8.11 mmol)in THF (50 mL) was added Pd(PPh₃)₄(0.170 g, 0.15 mmol), and the mixturewas stirred at room temperature for 3 hr under nitrogen atmosphere. Thereaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography (NH,solvent gradient; 5→25% ethyl acetate/hexane) to give an oil. This oilwas treated with 1N hydrochloric acid, and crystallized from EtOH/IPE togive2-(4-methoxyphenyl)-2-(methylamino)-N-(4-(trimethylsilyl)phenyl)acetamidehydrochloride (1.840 g, 4.86 mmol, 65.9%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.21 (9H, s), 2.45 (3H, s), 3.77 (3H, s),5.00 (1H, s), 6.97-7.10 (2H, m), 7.40-7.64 (6H, m), 9.44 (2H, brs),10.83 (1H, s).

(Step 4)

A solution of2-(4-methoxyphenyl)-2-(methylamino)-N-(4-(trimethylsilyl)phenyl)acetamidehydrochloride (100 mg, 0.29 mmol), 3-hydroxy-1,2-oxazole-5-carboxylicacid (45.2 mg, 0.35 mmol), DIEA (0.102 mL, 0.58 mmol) and HATU (133 mg,0.35 mmol) in DMF (2.0 mL) was stirred overnight at room temperature. Tothe reaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with water, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate), and crystallized from ethylacetate/hexane to give the title compound (84.8 mg, 0.187 mmol, 64.0%)as white crystals.

MS(API): Calculated 453.6, Found 452.0 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.22 (9H, s), 2.88 (3H, s), 3.76 (3H, s),6.18 (1H, s), 6.54 (1H, s), 7.00 (2H, d, J=8.7 Hz), 7.15-7.33 (2H, m),7.40-7.51 (2H, m), 7.52-7.68 (2H, m), 10.37 (1H, s), 11.32-12.19 (1H,m).

Example 13N-(1-(4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl)amino)ethyl)-5-oxopyrrolidine-3-carboxamide(Mixture of Four Optical Isomers)

(Step 1)

A solution of (4-methoxyphenyl)boronic acid (50 g, 329.04 mmol),diallylamine (32.0 g, 329.04 mmol) and glyoxylic acid monohydrate (30.3g, 329.04 mmol) in acetonitrile (300 mL) was stirred at 80° C. for 2 hr.The precipitate was suspended overnight in ethyl acetate (1000 mL) atroom temperature, and collected by filtration to give2-(diallylamino)-2-(4-methoxyphenyl)acetic acid (96 g, 366 mmol, 111%)as white crystals.

¹H NMR (300 MHz, CDCl₃): δ3.34 (2H, dd, J=14.0, 7.2 Hz), 3.65 (2H, dd,J=14.0, 6.4 Hz), 3.80 (3H, s), 4.63 (1H, s), 5.21-5.47 (4H, m),5.80-6.03 (2H, m), 6.88 (2H, d, J=8.7 Hz), 7.40 (2H, d, J=8.7 Hz)

(Step 2)

A solution of 2-(diallylamino)-2-(4-methoxyphenyl)acetic acid (200 mg,0.77 mmol), HATU (349 mg, 0.92 mmol), 4-(trimethylsilyl)aniline (152 mg,0.92 mmol) and TEA (0.127 mL, 0.92 mmol) in DMF (2 mL) was stirredovernight at room temperature. To the reaction mixture were added waterand ethyl acetate, and the organic layer was separated. The organiclayer was washed with water and brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure to give2-(diallylamino)-2-(4-methoxyphenyl)-N-(4-(trimethylsilyl)phenyl)acetamide(313 mg, 0.766 mmol, 100%) as an orange oil. This compound was used inthe next step without purification.

(Step 3)

A solution of2-(diallylamino)-2-(4-methoxyphenyl)-N-(4-(trimethylsilyl)phenyl)acetamide(313 mg, 0.77 mmol), Pd(PPh₃)₄ (35.4 mg, 0.03 mmol) and1,3-dimethylbarbituric acid (263 mg, 1.69 mmol) in THF (20 mL) wasstirred overnight at room temperature under nitrogen atmosphere. Thereaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography (NH,solvent gradient; 1→50% ethyl acetate/hexane) to give2-amino-2-(4-methoxyphenyl)-N-(4-(trimethylsilyl)phenyl)acetamide (100mg, 0.304 mmol, 39.7%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.24 (9H, s), 3.79 (3H, s), 4.60 (1H, s),6.84-6.92 (2H, m), 7.32-7.39 (2H, m), 7.45-7.49 (2H, m), 7.56-7.61 (2H,m), 9.32 (1H, brs).

(Step 4)

A solution of2-amino-2-(4-methoxyphenyl)-N-(4-(trimethylsilyl)phenyl)acetamide (100mg, 0.30 mmol), HATU (139 mg, 0.37 mmol), 5-oxopyrrolidine-3-carboxylicacid (47.2 mg, 0.37 mmol) and DIEA (0.064 mL, 0.37 mmol) in DMF (3 mL)was stirred overnight at room temperature. To the reaction mixture wereadded water and ethyl acetate, and the organic layer was separated. Theorganic layer was dried over sodium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (NH, solvent gradient; 1-60% ethylacetate/hexane) to give the title compound (70 mg, 0.159 mmol, 52.3%) asa white solid.

MS(API): Calculated 439.6, Found 438.2 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.20 (9H, s), 2.19-2.35 (2H, m), 3.09-3.27(1H, m), 3.34-3.52 (2H, m), 3.73 (3H, s), 5.44-5.64 (1H, m), 6.84-7.00(2H, m), 7.31-7.46 (4H, m), 7.48-7.62 (3H, m), 8.63-8.82 (1H, m),10.22-10.36 (1H, m).

Example 143-hydroxy-N-((1R)-1-(4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl)amino)ethyl)-N-methyl-1,2-oxazole-5-carboxamide

3-Hydroxy-N-(1-(4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl)amino)ethyl)-N-methyl-1,2-oxazole-5-carboxamide(15.8 g) was subjected to optical resolution using chiral columnchromatography. The preparative fraction having a shorter retention timewas concentrated to give the title compound (6.95 g) as a white solid.

MS(API): Calculated 453.6, Found 452.0 (M−H).

[α]_(D) ²⁵−171.9 (c 0.1930, MeOH)

purification condition using chiral column chromatography

column: CHIRALPAK AD(IL001)50 mmID×500 mmL

solvent: EtOH/acetic acid=1000/1

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

Example 15N-(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

A solution of2-(3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide)-2-(4-methoxyphenyl)aceticacid (100 mg, 0.33 mmol), 3-fluoro-4-(trimethylsilyl)aniline (65.8 mg,0.36 mmol), DIEA (0.114 mL, 0.65 mmol) and HATU (149 mg, 0.39 mmol) inDMF (2.0 mL) was stirred overnight at room temperature. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 0→50%ethyl acetate/hexane), and crystallized from ethyl acetate/hexane togive the title compound (5.6 mg, 0.012 mmol, 3.64%) as a white solid.

MS(API): Calculated 471.6, Found 470.0 (M−H).

¹H NMR (300 MHz, CDCl₃): δ0.28 (9H, s), 3.08 (3H, s), 3.83 (3H, s), 6.26(1H, s), 6.47 (1H, s), 6.91-6.98 (2H, m), 7.09 (1H, dd, J=7.9, 1.9 Hz),7.28-7.46 (4H, m), 7.68 (1H, brs).

Example 162-(4-methoxyphenyl)-2-(((6-oxo-1,6-dihydropyridin-3-yl)acetyl)amino)-N-(4-(trimethylsilyl)phenyl)acetamide

(Step 1)

A solution of2-amino-2-(4-methoxyphenyl)-N-(4-(trimethylsilyl)phenyl)acetamide (200mg, 0.61 mmol), 2-(6-methoxypyridin-3-yl)acetic acid (112 mg, 0.67mmol), DIEA (0.213 mL, 1.22 mmol) and HATU (278 mg, 0.73 mmol) in DMF(2.0 mL) was stirred overnight at room temperature. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure to give2-(4-methoxyphenyl)-2-(2-(6-methoxypyridin-3-yl)acetamide)-N-(4-(trimethylsilyl)phenyl)acetamide(226.2 mg, 0.474 mmol, 78%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.20 (9H, s), 3.51 (2H, s), 3.73 (3H, s),3.81 (3H, s), 5.55 (1H, d, J=7.2 Hz), 6.75 (1H, d, J=8.7 Hz), 6.93 (2H,d, J=8.3 Hz), 7.34-7.47 (4H, m), 7.51-7.65 (3H, m), 8.02 (1H, s), 8.84(1H, d, J=7.6 Hz), 10.28 (1H, s).

(Step 2)

A solution of2-(4-methoxyphenyl)-2-(2-(6-methoxypyridin-3-yl)acetamide)-N-(4-(trimethylsilyl)phenyl)acetamide(220 mg, 0.46 mmol), sodium iodide (207 mg, 1.38 mmol) and TMSCl (0.177mL, 1.38 mmol) in acetonitrile (6.0 mL) was stirred at 70° C. for 2 hr.To the reaction mixture were added water and ethyl acetate, and theorganic layer was separated. The organic layer was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent; ethyl acetate), and crystallized from ethyl acetate/hexane togive the title compound (30.2 mg, 0.065 mmol, 14.14%) as white crystals.

MS(API): Calculated 463.6, Found 464.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ3.30 (2H, brs), 3.73 (3H, s), 5.54 (1H, d,J=7.6 Hz), 6.26 (1H, d, J=9.1 Hz), 6.92 (2H, d, J=8.7 Hz), 7.21 (1H, s),7.28-7.46 (5H, m), 7.55 (2H, d, J=8.3 Hz), 8.73 (1H, d, J=7.6 Hz), 10.28(1H, s), 11.39 (1H, brs).

Example 17N-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

(Step 1)

To a solution of 2-(allyl(methyl)amino)-2-(4-methoxyphenyl)acetic acid(5.0 g, 21.25 mmol) in a mixed solvent of MeOH (50 mL) and toluene (100mL) was added 0.6M trimethylsilyldiazomethane hexane solution (49.6 mL,29.75 mmol) at room temperature, and the mixture was stirred for 1 hr.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(solvent; ethyl acetate/hexane) to give methyl2-(allyl(methyl)amino)-2-(4-methoxyphenyl)acetate (4.48 g, 17.97 mmol,85%) as a colorless oil.

MS(API): Calculated 249.3, Found 250.2 (M+H).

(Step 2)

To a solution of methyl2-(allyl(methyl)amino)-2-(4-methoxyphenyl)acetate (4.48 g, 17.97 mmol)and 1,3-dimethylbarbituric acid (3.09 g, 19.77 mmol) in THF (70 mL) wasadded Pd(PPh₃)₄(0.415 g, 0.36 mmol), and the mixture was stirred at roomtemperature for 3 hr under nitrogen atmosphere. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;5→25% ethyl acetate/hexane) to give methyl2-(4-methoxyphenyl)-2-(methylamino)acetate (3.74 g, 17.87 mmol, 99%) asa colorless oil.

(Step 3)

A solution of methyl 2-(4-methoxyphenyl)-2-(methylamino)acetate (3.74 g,17.87 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (2.54 g, 19.66mmol), DIEA (6.24 mL, 35.75 mmol) and HATU (8.16 g, 21.45 mmol) in DMF(100 mL) was stirred overnight at room temperature. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 0→50%ethyl acetate/hexane) to give methyl2-(3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide)-2-(4-methoxyphenyl)acetate(2.41 g, 7.52 mmol, 42.1%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ2.90 (3H, s), 2.98 (3H, s), 3.83 (3H, s), 6.29(1H, s), 6.47 (1H, s), 6.88-6.96 (2H, m), 7.17-7.25 (2H, m), 8.04 (1H,s).

(Step 4)

To a solution of methyl2-(3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide)-2-(4-methoxyphenyl)acetate(2.41 g, 7.52 mmol) in a mixed solvent of MeOH (24 mL) and THF (24.00mL) was added 1N aqueous sodium hydroxide solution (15.05 mL, 15.05mmol), and the mixture was stirred overnight at room temperature. To thereaction mixture was added water, and the pH of the mixture was adjustedto 2-3 with 1N hydrochloric acid. The mixture was extracted with ethylacetate, and the organic layer was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure to give2-(3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide)-2-(4-methoxyphenyl)aceticacid (2.15 g, 7.02 mmol, 93%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ2.64-2.94 (3H, m), 3.77 (3H, s), 5.64-6.01(1H, m), 6.42-6.58 (1H, m), 6.91-7.05 (2H, m), 7.17-7.34 (2H, m), 11.74(1H, brs), 13.22 (1H, brs).

(Step 5)

A solution of2-(3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide)-2-(4-methoxyphenyl)aceticacid (100 mg, 0.33 mmol), 3,5-difluoro-4-(trimethylsilyl)aniline (79 mg,0.39 mmol), DIEA (0.285 mL, 1.63 mmol) and T3P (0.408 mL, 0.65 mmol) inDMF (2.0 mL) was stirred at 80° C. for 3 hr. To the reaction mixturewere added water and ethyl acetate, and the organic layer was separated.The organic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→50% ethylacetate/hexane) to give the title compound (15.4 mg, 0.031 mmol, 9.63%)as a white solid.

MS(API): Calculated 489.5, Found 490.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.32 (9H, s), 2.74-2.94 (3H, m), 3.77 (3H,s), 5.72-6.15 (1H, m), 6.39-6.59 (1H, m), 7.01 (2H, d, J=8.7 Hz),7.16-7.34 (4H, m), 10.55-10.79 (1H, m), 11.80 (1H, brs).

Example 182-(4-methoxyphenyl)-2-(((3-methyl-1,2-oxazol-5-yl)acetyl)amino)-N-(4-(trimethylsilyl)phenyl)acetamide

A solution of2-amino-2-(4-methoxyphenyl)-N-(4-(trimethylsilyl)phenyl)acetamide (100mg, 0.30 mmol), 2-(3-methyl-1,2-oxazol-5-yl)acetic acid (51.6 mg, 0.37mmol), HATU (150 mg, 0.40 mmol) and DIEA (0.106 mL, 0.61 mmol) in DMF (3mL) was stirred at room temperature for 10 hr. To the reaction mixturewere added water and ethyl acetate, and the organic layer was separated.The organic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 20-50% ethylacetate/hexane), and crystallized from ethyl acetate/hexane to give thetitle compound (113 mg, 0.250 mmol, 82%) as white crystals.

MS(API): Calculated 451.6, Found 452.2 (M+H).

Example 192-(4-methoxyphenyl)-2-(((1-methyl-1H-pyrazol-3-yl)acetyl)amino)-N-(4-(trimethylsilyl)phenyl)acetamide

A solution of2-amino-2-(4-methoxyphenyl)-N-(4-(trimethylsilyl)phenyl)acetamide (100mg, 0.30 mmol), 2-(1-methyl-1H-pyrazol-3-yl)acetic acid (51.2 mg, 0.37mmol), HATU (150 mg, 0.40 mmol) and DIEA (0.106 mL, 0.61 mmol) in DMF(1.5 mL) was stirred at room temperature for 10 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure, and crystallized fromethyl acetate to give the title compound (99 mg, 0.219 mmol, 71.9%) aswhite crystals.

MS(API): Calculated 450.6, Found 451.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.20 (9H, s), 3.51 (2H, s), 3.73 (3H, s),3.76 (3H, s), 5.56 (1H, d, J=7.6 Hz), 6.08 (1H, d, J=1.9 Hz), 6.92 (2H,d, J=8.7 Hz), 7.35-7.47 (4H, m), 7.51-7.60 (3H, m), 8.67 (1H, d, J=7.6Hz), 10.28 (1H, s).

Example 202-(4-methoxyphenyl)-2-(((1-methyl-1H-pyrazol-4-yl)acetyl)amino)-N-(4-(trimethylsilyl)phenyl)acetamide

A solution of2-amino-2-(4-methoxyphenyl)-N-(4-(trimethylsilyl)phenyl)acetamide (100mg, 0.30 mmol), 2-(1-methyl-1H-pyrazol-4-yl)acetic acid (51.2 mg, 0.37mmol), HATU (150 mg, 0.40 mmol) and DIEA (0.106 mL, 0.61 mmol) in DMF (3mL) was stirred at room temperature for 10 hr. To the reaction mixturewere added water and ethyl acetate, and the organic layer was separated.The organic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 75→99% ethylacetate/hexane) to give the title compound (83 mg, 0.183 mmol, 60.2%) aswhite crystals.

MS(API): Calculated 450.6, Found 451.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.20 (9H, s), 3.36 (2H, s), 3.72 (3H, s),3.76 (3H, s), 5.55 (1H, d, J=7.9 Hz), 6.92 (2H, d, J=8.7 Hz), 7.25 (1H,s), 7.34-7.60 (7H, m), 8.63 (1H, d, J=7.6 Hz), 10.28 (1H, s).

Example 21N-(2-((2,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

(Step 1)

A solution of 1-bromo-2,5-difluoro-4-nitrobenzene (3.0 g, 12.61 mmol),HMDS (3.10 mL, 15.13 mmol), Pd₂(dba)₃ (0.173 g, 0.19 mmol),2′-(di-tert-butylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (0.387g, 1.13 mmol), water (0.454 g, 25.21 mmol) and lithium acetate (4.16 g,63.03 mmol) in DMF (60 mL) was stirred at 100° C. for 24 hr under argongas atmosphere. To the reaction mixture were added water and ethylacetate, and the organic layer was separated. The organic layer wasdried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→5% ethyl acetate/hexane) to give(2,5-difluoro-4-nitrophenyl)trimethylsilane (745.9 mg, 3.23 mmol,25.61%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.36 (9H, d, J=0.8 Hz), 7.27-7.33 (1H, m),7.64-7.72 (1H, m).

(Step 2)

A solution of (2,5-difluoro-4-nitrophenyl)trimethylsilane (740 mg, 3.20mmol) and 10% palladium on carbon (74 mg, 0.70 mmol) in MeOH (15 mL) wasstirred at room temperature for 5 hr under hydrogen atmosphere (1 atm).The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure to give2,5-difluoro-4-(trimethylsilyl)aniline as an oil. This compound wasdirectly used in the next step.

(Step 3)

A solution of2-(3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide)-2-(4-methoxyphenyl)aceticacid (200 mg, 0.65 mmol), 2,5-difluoro-4-(trimethylsilyl)aniline (158mg, 0.78 mmol), DIEA (0.570 mL, 3.27 mmol) and T3P (0.816 mL, 1.31 mmol)in DMF (2.0 ML) was stirred at 80° C. for 5 hr. To the reaction mixturewere added water and ethyl acetate, and the organic layer was separated.The organic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→5% ethylacetate/hexane) to give the title compound (11.3 mg, 0.023 mmol, 3.53%)as a pale yellow solid.

MS(API): Calculated 489.5, Found 488.0 (M−H).

¹H NMR (300 MHz, CDCl₃): δ0.28 (9H, s), 3.07 (3H, brs), 3.83 (3H, s),6.30 (1H, brs), 6.48 (1H, s), 6.87-7.09 (3H, m), 7.36 (2H, d, J=7.9 Hz),7.77 (1H, brs), 8.07 (1H, dd, J=9.3, 5.9 Hz).

Example 222-(4-(methoxymethyl)phenyl)-2-(((1-methyl-1H-pyrazol-4-yl)acetyl)amino)-N-(4-(trimethylsilyl)phenyl)acetamide

(Step 1)

A solution of (4-(methoxymethyl)phenyl)boronic acid (999 mg, 6.02 mmol),glyoxylic acid monohydrate (554 mg, 6.02 mmol) and diallylamine (0.741mL, 6.02 mmol) in acetonitrile (12 mL) was stirred at 60° C. for 5 hr.The reaction mixture was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography (Diol,solvent; ethyl acetate), and crystallized from ethyl acetate to give2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid (200 mg, 0.726mmol, 12.07%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ3.04-3.46 (7H, m), 4.39 (2H, s), 4.43 (1H,s), 5.04-5.23 (4H, m), 5.78 (2H, ddt, J=16.9, 10.5, 6.3 Hz), 7.23-7.40(4H, m).

(Step 2)

A solution of 2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid(200 mg, 0.73 mmol), 4-(trimethylsilyl)aniline (132 mg, 0.80 mmol), HATU(331 mg, 0.87 mmol) and DIEA (0.254 mL, 1.45 mmol) in DMF (3 mL) wasstirred at room temperature for 1 hr. To the reaction mixture were addedwater and ethyl acetate, and the organic layer was separated. Theorganic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 1→25% ethylacetate/hexane) to give2-(diallylamino)-2-(4-(methoxymethyl)phenyl)-N-(4-(trimethylsilyl)phenyl)acetamide(150 mg, 0.355 mmol, 48.9%) as a yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ0.16-0.25 (9H, m), 3.04-3.14 (2H, m),3.18-3.29 (5H, m), 4.39 (2H, s), 4.52 (1H, s), 5.07-5.22 (4H, m), 5.85(2H, ddt, J=16.8, 10.4, 6.2 Hz), 7.30 (2H, d, J=7.9 Hz), 7.43 (4H, d,J=7.9 Hz), 7.61 (2H, d, J=8.7 Hz), 10.07 (1H, s).

(Step 3)

To a solution of2-(diallylamino)-2-(4-(methoxymethyl)phenyl)-N-(4-(trimethylsilyl)phenyl)acetamide(150 mg, 0.35 mmol) and 1,3-dimethylbarbituric acid (122 mg, 0.78 mmol)in THF (3 mL) was added Pd(PPh₃)₄(16.41 mg, 0.01 mmol) at roomtemperature under argon gas atmosphere, and the mixture was stirred for6 hr. The reaction mixture was concentrated under reduced pressure, andthe obtained residue was purified by silica gel column chromatography(solvent gradient; 40-80% MeOH/ethyl acetate) to give2-amino-2-(4-(methoxymethyl)phenyl)-N-(4-(trimethylsilyl)phenyl)acetamide(104 mg, 0.304 mmol, 865) as a yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ0.15-0.24 (9H, m), 3.26 (3H, s), 4.37 (2H,s), 4.52 (1H, s), 7.26 (2H, d, J=8.3 Hz), 7.35-7.47 (4H, m), 7.57-7.64(2H, m), 10.06 (1H, brs).

(Step 4)

A solution of2-amino-2-(4-(methoxymethyl)phenyl)-N-(4-(trimethylsilyl)phenyl)acetamide(104 mg, 0.30 mmol), 2-(1-methyl-1H-pyrazol-4-yl)acetic acid (51.1 mg,0.36 mmol), HATU (150 mg, 0.39 mmol) and DIEA (0.106 mL, 0.61 mmol) inDMF (1.5 mL) was stirred at room temperature for 10 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 40→80%ethyl acetate/hexane), and crystallized from ethyl acetate/hexane togive the title compound (45.0 mg, 0.097 mmol, 31.9%) as white crystals.

MS(API): Calculated 464.6, Found 465.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.17-0.22 (9H, m), 3.31 (3H, s), 3.38 (2H,s), 3.76 (3H, s), 4.37 (2H, s), 5.63 (1H, d, J=7.9 Hz), 7.24-7.34 (3H,m), 7.39-7.60 (7H, m), 8.71 (1H, d, J=7.9 Hz), 10.35 (1H, s).

Example 23N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide(750.5 mg) was subjected to optical resolution using chiral columnchromatography. The preparative fraction having a shorter retention timewas concentrated to give the title compound (292.2 mg, >99.9% ee) as awhite solid.

MS(API): Calculated 489.5, Found 488.0 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.32 (9H, s), 2.75-2.91 (3H, m), 3.77 (3H,s), 5.72-6.16 (1H, m), 6.39-6.59 (1H, m), 7.01 (2H, d, J=8.7 Hz),7.14-7.32 (4H, m), 10.55-10.80 (1H, m), 11.79 (1H, brs).

purification condition using chiral column chromatography

column: CHIRALPAK IA(NL001)50 mmID×500 mmL

solvent: hexane/EtOH/acetic acid=500/500/1

flow rate: 60 mL/min

temperature: 30° C.

detection method: UV 220 nm

[α]_(D) ²⁵−132.7 (c 0.2345, MeOH)

Example 24N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

N-(2-((3-Fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide(80 mg) was subjected to optical resolution using chiral columnchromatography. The preparative fraction having a shorter retention timewas concentrated to give the title compound (32.2 mg, >99.9% ee) as awhite solid.

MS(API): Calculated 471.6, Found 470.0 (M−H).

purification condition using chiral column chromatography

column: CHIRAPAK AD(NL001)50 mmID×500 mmL

solvent: hexane/EtOH/acetic acid 300/700/1

flow rate: 60 mL/min

temperature: 30° C.

detection method: UV 220 nm

[α]_(D) ²⁵ 179.8 (c 0.2250, MeOH)

Example 25N-((1R)-2-((2,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

N-(2-((2,5-Difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide(120 mg) was subjected to optical resolution using chiral columnchromatography. The preparative fraction having a shorter retention timewas concentrated to give the title compound (38.9 mg, >99.9% ee) as awhite solid.

MS(API): Calculated 489.5, Found 488.0 (M−H).

purification condition using chiral column chromatography

column: CHIRALPAK IA(NL001) 50 mmID×500 mmL

solvent: hexane/EtOH/acetic acid 300/700/1

flow rate: 60 mL/min

temperature: 30° C.

detection method: UV 220 nm

[α]_(D) ²⁵−162.4 (c 0.1960, MeOH)

Example 26N-(2-((3-cyano-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide(Mixture of Four Optical Isomers)

(Step 1)

A solution of 2-chloro-5-nitrobenzonitrile (19.5 g, 106.81 mmol), HMDS(43.7 mL, 213.62 mmol), Pd₂(dba)₃ (2.93 g, 3.20 mmol),2′-(di-tert-butylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (3.28g, 9.61 mmol), water (3.85 g, 213.62 mmol) and lithium acetate (35.2 g,534.06 mmol) in DMF (400 mL) was stirred at 100° C. for 5 hr under argongas atmosphere. To the reaction mixture were added water and ethylacetate, and the organic layer was separated. The organic layer wasdried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→5% ethyl acetate/hexane) to give5-nitro-2-(trimethylsilyl)benzonitrile (13.2 g, 59.9 mmol, 56.1%) as awhite solid.

(Step 2)

A solution of 5-nitro-2-(trimethylsilyl)benzonitrile and 10%palladium-carbon (1.32 g, 0.62 mmol, 50% wet) in MeOH (260 mL) wasstirred at room temperature for 5 hr under hydrogen atmosphere (1 atm).The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 10→20% ethylacetate/hexane) to give 5-amino-2-(trimethylsilyl)benzonitrile (9.56 g,50.2 mmol, 84%) as a white solid.

(Step 3)

A solution of 2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid(1186 mg, 4.31 mmol), 5-amino-2-(trimethylsilyl)benzonitrile (820 mg,4.31 mmol), T3P (3.80 mL, 6.46 mmol), DIEA (3.84 mL, 21.54 mmol) andDMAP (526 mg, 4.31 mmol) in ethyl acetate (20 mL) was stirred overnightat 80° C. To the reaction mixture were added water and ethyl acetate,and the organic layer was separated. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 10→100% ethyl acetate/hexane)to giveN-(3-cyano-4-(trimethylsilyl)phenyl)-2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetamide(2890 mg, 6.46 mmol, 150%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.32-0.50 (9H, m), 2.89 (2H, dd, J=14.7, 7.2Hz), 3.25-3.39 (2H, m), 3.38-3.51 (3H, m), 4.36-4.64 (3H, m), 5.18-5.41(4H, m), 5.65-6.04 (2H, m), 7.27-7.38 (4H, m), 7.54 (1H, d, J=8.3 Hz),7.78 (1H, dd, J=8.3, 2.3 Hz), 7.91 (1H, d, J=2.3 Hz), 9.57 (1H, s).

(Step 4)

A solution ofN-(3-cyano-4-(trimethylsilyl)phenyl)-2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetamide(2.89 g, 6.46 mmol), 1,3-dimethylbarbituric acid (2.218 g, 14.20 mmol)and Pd(PPh₃)₄(0.298 g, 0.26 mmol) in THE (40 mL) was stirred overnightat room temperature under nitrogen atmosphere. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;10→100% ethyl acetate/hexane) to give2-amino-N-(3-cyano-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(2.180 g, 5.93 mmol, 92%) as a brown oil.

¹H NMR (300 MHz, DMSO-d₆): δ0.35 (9H, s), 3.26 (3H, s), 4.37 (2H, s),7.22-7.36 (2H, m), 7.44 (2H, d, J=8.3 Hz), 7.50-7.67 (5H, m), 7.85 (1H,dd, J=8.3, 1.9 Hz), 8.15 (1H, d, J=1.9 Hz).

(Step 5)

A solution of2-amino-N-(3-cyano-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(290 mg, 0.79 mmol), 5-oxopyrrolidine-3-carboxylic acid (112 mg, 0.87mmol), HATU (330 mg, 0.87 mmol) and DIEA (0.152 mL, 0.87 mmol) in DMF (5mL) was stirred overnight at room temperature. To the reaction mixturewere added water and ethyl acetate, and the organic layer was separated.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 10→100% ethyl acetate/hexane, 1→15% MeOH/ethylacetate) to give the title compound (50.0 mg, 0.104 mmol, 13.24%) as awhite solid.

MS(API): Calculated 478.6, Found 479.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.34 (9H, d, J=1.5 Hz), 2.26 (2H, d, J=7.6Hz), 3.27 (4H, d, J=1.9 Hz), 3.36-3.55 (2H, m), 4.38 (2H, s), 5.58 (1H,d, J=7.2 Hz), 7.32 (2H, d, J=7.6 Hz), 7.38-7.66 (4H, m), 7.67-7.83 (1H,m), 8.10 (1H, s), 8.81 (1H, d, J=7.2 Hz), 10.70 (1H, s).

Example 27N-(2-((3-cyano-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide(Mixture of Four Optical Isomers)

(Step 1)

A solution of 2-(diallylamino)-2-(4-methoxyphenyl)acetic acid (2.060 g,7.88 mmol), 5-amino-2-(trimethylsilyl)benzonitrile (1.5 g, 7.88 mmol),T3P (7.39 mL, 11.82 mmol), DIEA (6.88 mL, 39.41 mmol) and DMAP (1.059 g,8.67 mmol) in ethyl acetate (20 mL) was stirred overnight at 80° C. Tothe reaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→100% ethyl acetate/hexane) to giveN-(3-cyano-4-(trimethylsilyl)phenyl)-2-(diallylamino)-2-(4-methoxyphenyl)acetamide(2.000 g, 4.61 mmol, 58.5%) as a yellow oil.

(Step 2)

A solution ofN-(3-cyano-4-(trimethylsilyl)phenyl)-2-(diallylamino)-2-(4-methoxyphenyl)acetamide(3 g, 6.92 mmol), 1,3-dimethylbarbituric acid (2.377 g, 15.22 mmol) andPd(PPh₃)₄ (0.320 g, 0.28 mmol) in THF (50 mL) was stirred overnight atroom temperature under nitrogen atmosphere. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;10→100% ethyl acetate/hexane) to give2-amino-N-(3-cyano-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(2.000 g, 5.66 mmol, 82%) as a pale yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ0.35 (9H, s), 3.72 (3H, s), 4.44-4.60 (1H,m), 6.89 (2H, d, J=8.7 Hz), 7.24-7.44 (2H, m), 7.49-7.71 (2H, m), 7.85(1H, dd, J=8.3, 1.9 Hz), 8.16 (1H, d, J=2.3 Hz) (NH₂ D peak was notobserved.).

(Step 3)

A solution of2-amino-N-(3-cyano-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(400 mg, 1.13 mmol), 5-oxopyrrolidine-3-carboxylic acid (146 mg, 1.13mmol), HATU (430 mg, 1.13 mmol) and DMAP (0.198 mL, 1.13 mmol) in DMF (5mL) was stirred overnight at room temperature. To the reaction mixturewere added water and ethyl acetate, and the organic layer was separated.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 10→100% ethyl acetate/hexane, 1→10% MeOH/ethylacetate) to give the title compound (452 mg, 0.973 mmol, 86%) as a whitesolid.

MS(API): Calculated 464.6, Found 463.0 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.24-0.53 (9H, m), 2.29 (2H, dd, J=14.5, 8.5Hz), 3.13-3.30 (1H, m), 3.37-3.50 (2H, m), 3.74 (3H, s), 5.51 (1H, t,J=6.8 Hz), 6.95 (2H, dd, J=8.7, 1.1 Hz), 7.39 (2H, d, J=9.1 Hz),7.50-7.66 (2H, m), 7.74 (1H, ddd, J=8.3, 3.8, 2.3 Hz), 8.10 (1H, t,J=2.3 Hz), 8.76 (1H, t, J=7.6 Hz), 10.64 (1H, d, J=3.4 Hz).

Example 28N-(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide(Mixture of Four Optical Isomers)

(Step 1)

To a solution of 3-fluoro-4-(trimethylsilyl)aniline (500 mg, 2.73 mmol),2-(diallylamino)-2-(4-methoxyphenyl)acetic acid (784 mg, 3.00 mmol),DMAP (367 mg, 3.00 mmol) and DIEA (2.382 mL, 13.64 mmol) in ethylacetate (15 mL) was added T3P (2.407 mL, 4.09 mmol), and the mixture wasstirred at 80° C. for 2 hr. To the reaction mixture were added water andethyl acetate, and the organic layer was separated. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 5→50% ethylacetate/hexane) to give2-(diallylamino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(935 mg, 2.192 mmol, 80%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.13-0.47 (9H, m), 2.89 (2H, dd, J=14.7, 7.2Hz), 3.32 (2H, dd, J=14.7, 5.3 Hz), 3.80 (3H, s), 4.49 (1H, s),5.12-5.35 (4H, m), 5.73-6.00 (2H, m), 6.81-6.98 (2H, m), 7.13-7.37 (4H,m), 7.45 (1H, dd, J=10.6, 1.9 Hz), 9.49 (1H, s).

(Step 2)

A solution of2-(diallylamino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(900 mg, 2.11 mmol), 1,3-dimethylbarbituric acid (692 mg, 4.43 mmol) andPd(PPh₃)₄ (98 mg, 0.08 mmol) in THE (8 mL) was stirred at roomtemperature for 3 days under nitrogen atmosphere. The reaction mixturewas concentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;5→75% ethyl acetate/hexane) to give2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(679 mg, 1.959 mmol, 93%) as a white oil.

¹H NMR (300 MHz, CDCl₃): δ0.28 (9H, s), 1.88 (2H, brs), 3.79 (3H, s),4.59 (1H, s), 6.79-6.97 (2H, m), 7.14-7.38 (4H, m), 7.38-7.51 (1H, m),9.45 (1H, brs).

(Step 3)

A solution of2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(350 mg, 1.01 mmol), 5-oxopyrrolidine-3-carboxylic acid (150 mg, 1.16mmol), HOBt (77 mg, 0.51 mmol), TEA (0.422 mL, 3.03 mmol) and WSC (235mg, 1.52 mmol) in DMF (4 mL) was stirred overnight at room temperature.To the reaction mixture were added water and ethyl acetate, and theorganic layer was separated. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→100% ethyl acetate/hexane) to givethe title compound (392 mg, 0.856 mmol, 85%) as a white solid.

MS(API): Calculated 457.6, Found 456.0 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.22-0.40 (9H, m), 2.16-2.40 (2H, m),3.08-3.28 (1H, m), 3.33-3.55 (2H, m), 3.73 (3H, s), 5.52 (1H, t, J=6.8Hz), 6.94 (2H, dd, J=8.7, 1.1 Hz), 7.19-7.44 (4H, m), 7.44-7.61 (2H, m),8.75 (1H, t, J=7.6 Hz), 10.51 (1H, d, J=3.8 Hz).

Example 29N-(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxypyrrolidine-1-carboxamide(Mixture of Four Optical Isomers)

(Step 1)

To a solution of2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(350 mg, 1.01 mmol) in THF (6 mL) were added p-nitrophenyl chloroformate(234 mg, 1.16 mmol) and pyridine (0.094 mL, 1.16 mmol), and the mixturewas stirred at room temperature for 1 hr. To the reaction mixture wereadded water and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with water, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure to give4-nitrophenyl(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)carbamate(560 mg, 1.095 mmol, 1081) as a pale yellow solid.

(Step 2)

A solution of DL-3-pyrrolidinol (0.128 mL, 1.58 mmol) and DIEA (0.553mL, 3.17 mmol) in DMF (2 mL) was added to a solution of 4-nitrophenyl(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)carbamate(270 mg, 0.53 mmol) in DMF (2.000 mL), and the mixture was stirredovernight at room temperature. To the reaction mixture were added waterand ethyl acetate, and the organic layer was separated. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 10→100%ethyl acetate/hexane, 0→15% MeOH/ethyl acetate) to give the titlecompound (18.80 mg, 0.041 mmol, 7.753) as a pale yellow solid.

MS(API): Calculated 459.6, Found 460.3 (M+H).

¹H NMR (300 MHz, CDCl₃): δ0.13-0.38 (9H, m), 1.64-1.88 (2H, m),1.88-2.12 (2H, m), 3.38-3.53 (3H, m), 3.69-3.88 (3H, m), 4.29-4.55 (1H,m), 5.50-5.76 (2H, m), 6.70-6.90 (2H, m), 7.06-7.46 (5H, m), 9.23 (1H,d, J=8.3 Hz).

Example 30N-(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxyazetidine-1-carboxamide

A solution of azetidin-3-ol hydrochloride (289 mg, 2.64 mmol) and DIEA(1.383 mL, 7.92 mmol) in DMF (2 mL) was added to a solution of4-nitrophenyl(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)carbamate(270 mg, 0.53 mmol) in DMF (2.000 mL), and the mixture was stirredovernight at room temperature. To the reaction mixture were added waterand ethyl acetate, and the organic layer was separated. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 10→100%ethyl acetate/hexane, 0→15% MeOH/ethyl acetate) to give the titlecompound (55.8 mg, 0.125 mmol, 23.733) as a white solid.

MS(API): Calculated 445.6, Found 446.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.10-0.28 (9H, m), 3.51-3.68 (2H, m), 3.73(3H, s), 3.93-4.15 (2H, m), 4.27-4.49 (1H, m), 5.39 (1H, d, J=7.9 Hz),5.56 (1H, d, J=6.4 Hz), 6.75 (1H, d, J=7.9 Hz), 6.91 (2H, d, J=8.7 Hz),7.21-7.45 (4H, m), 7.45-7.60 (1H, m), 10.40 (1H, s).

Example 31N-(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

(Step 1)

A solution of (4-(methoxymethyl)phenyl)boronic acid (11.67 g, 70.30mmol), glyoxylic acid monohydrate (6.47 g, 70.30 mmol) andN-methyl-2-propen-1-amine (6.75 mL, 70.30 mmol) in acetonitrile (150 mL)was stirred overnight at 50° C. The reaction mixture was concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (Diol, solvent gradient; 5→100% ethylacetate/hexane) to give2-(allyl(methyl)amino)-2-(4-(methoxymethyl)phenyl)acetic acid (7.20 g,28.9 mmol, 41.1%) as a pale yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ2.22 (3H, s), 3.13 (2H, t, J=5.7 Hz), 3.29(3H, s), 4.19 (1H, s), 4.40 (2H, s), 5.04-5.40 (2H, m), 5.65-6.12 (1H,m), 7.23-7.34 (2H, m), 7.34-7.43 (2H, m). (COOH D peak was notobserved.)

(Step 2)

To a solution of 3-fluoro-4-(trimethylsilyl)aniline (1.0 g, 5.46 mmol),2-(allyl(methyl)amino)-2-(4-(methoxymethyl)phenyl)acetic acid (1.496 g,6.00 mmol), DMAP (0.733 g, 6.00 mmol) and DIEA (4.76 mL, 27.28 mmol) inethyl acetate (30 mL) was added T3P (4.81 mL, 8.18 mmol), and themixture was stirred at 80° C. for 1 hr. To the reaction mixture wereadded water and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 5-50% ethyl acetate/hexane) to give2-(allyl(methyl)amino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(2.140 g, 5.16 mmol, 95%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.17-0.32 (9H, m), 2.21 (3H, s), 2.90-3.20(2H, m), 3.32-3.42 (3H, m), 4.13-4.24 (1H, m), 4.44 (2H, s), 5.17-5.32(2H, m), 5.75-6.00 (1H, m), 7.13-7.39 (6H, m), 7.44 (1H, dd, J=10.4, 1.7Hz), 9.32 (1H, s).

(Step 3)

A solution of2-(allyl(methyl)amino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(2.05 g, 4.94 mmol), 1,3-dimethylbarbituric acid (1.158 g, 7.42 mmol)and Pd(PPh₃)₄ (0.114 g, 0.10 mmol) in THF (18 mL) was stirred overnightat room temperature under nitrogen atmosphere. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;5→75% ethyl acetate/hexane) to giveN-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(methylamino)acetamide(1.828 g, 4.88 mmol, 99%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ0.28 (9H, s), 2.53 (3H, s), 3.36 (3H, s),4.10-4.20 (1H, m), 4.43 (2H, s), 7.15-7.41 (6H, m), 7.46 (1H, dd,J=10.4, 1.7 Hz), 9.39 (1H, s) (The peak of NH was not observed.).

(Step 4)

To a solution ofN-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(methylamino)acetamide(620 mg, 1.66 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (246 mg,1.90 mmol), HOBt (127 mg, 0.83 mmol), DMAP (20.22 mg, 0.17 mmol) and TEA(0.692 mL, 4.97 mmol) in DMF (10 mL) was added WSC (476 mg, 2.48 mmol),and the mixture was stirred at 80° C. for 1.5 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→100% ethyl acetate/hexane, 0→15%MeOH/ethyl acetate) to give the title compound (527 mg, 1.086 mmol,65.6%) as a white solid.

MS(API): Calculated 485.6, Found 484.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.11-0.30 (9H, m), 2.67-2.86 (1H, m), 2.89(3H, s), 3.36-3.45 (2H, m), 4.31-4.56 (2H, m), 5.79-6.30 (1H, m),6.37-6.63 (1H, m), 7.15-7.48 (6H, m), 7.56 (1H, d, J=11.3 Hz),10.45-10.75 (1H, m).

Example 32N-(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide(Mixture of Four Optical Isomers)

(Step 1)

To a solution of 3-fluoro-4-(trimethylsilyl)aniline (1.0 g, 5.46 mmol),2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid (1.652 g, 6.00mmol), DMAP (0.733 g, 6.00 mmol) and DIEA (4.76 mL, 27.28 mmol) in ethylacetate (30 mL) was added T3P (4.81 mL, 8.18 mmol), and the mixture wasstirred at 80° C. for 1 hr. To the reaction mixture were added water andethyl acetate, and the organic layer was separated. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 5→35% ethylacetate/hexane) to give2-(diallylamino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(1.890 g, 4.29 mmol, 79%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.20-0.36 (9H, m), 2.88 (2H, dd, J=14.7, 7.2Hz), 3.25-3.46 (5H, m), 4.41-4.50 (2H, m), 4.55 (1H, s), 5.16-5.35 (4H,m), 5.74-5.97 (2H, m), 7.12-7.38 (6H, m), 7.44 (1H, dd, J=10.4, 1.7 Hz),9.48 (1H, s).

(Step 2)

A solution of2-(diallylamino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(1.80 g, 4.09 mmol), 1,3-dimethylbarbituric acid (1.339 g, 8.58 mmol)and Pd(PPh₃)₄(0.189 g, 0.16 mmol) in THF (18 mL) was stirred overnightat room temperature under nitrogen atmosphere. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;5-75% ethyl acetate/hexane) to give2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(1.085 g, 3.01 mmol, 73.7%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.25-0.43 (9H, m), 1.88 (2H, brs), 3.37 (3H,s), 4.43 (2H, s), 4.63 (1H, s), 7.15-7.36 (4H, m), 7.36-7.51 (3H, m),9.48 (1H, brs).

(Step 3)

A solution of2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(220 mg, 0.61 mmol), 5-oxopyrrolidine-3-carboxylic acid (91 mg, 0.70mmol), HOBt (46.7 mg, 0.31 mmol), TEA (0.255 mL, 1.83 mmol) and WSC (142mg, 0.92 mmol) in DMF (4 mL) was stirred overnight at room temperature.To the reaction mixture were added water and ethyl acetate, and theorganic layer was separated. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→100% ethyl acetate/hexane, 0→15%MeOH/ethyl acetate) to give the title compound (198 mg, 0.420 mmol,68.8%) as a white solid.

MS(API): Calculated 471.6, Found 470.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 2.12-2.40 (2H, m), 3.10-3.30(4H, m), 3.33-3.55 (2H, m), 4.38 (2H, s), 5.60 (1H, t, J=6.8 Hz),7.18-7.39 (4H, m), 7.39-7.65 (4H, m), 8.83 (1H, t, J=7.7 Hz), 10.58 (1H,d, J=4.2 Hz).

Example 33N-(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxypyrrolidine-1-carboxamide(Mixture of Four Optical Isomers)

(Step 1)

To a solution of2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(390 mg, 1.08 mmol) in THF (6 mL) were added p-nitrophenyl chloroformate(251 mg, 1.24 mmol) and pyridine (0.100 mL, 1.24 mmol), and the mixturewas stirred at room temperature for 1 hr. To the reaction mixture wereadded water and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with water, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure to give4-nitrophenyl(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(476 mg, 0.906 mmol, 84%) as a pale yellow solid.

(Step 2)

A solution of DL-3-pyrrolidinol (0.106 mL, 1.31 mmol) and DIEA (0.459mL, 2.63 mmol) in DMF (2 mL) was added to a solution of 4-nitrophenyl(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(230 mg, 0.44 mmol) in DMF (2.000 mL), and the mixture was stirredovernight at room temperature. To the reaction mixture were added waterand ethyl acetate, and the organic layer was separated. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 10→100%ethyl acetate/hexane, 0→15% MeOH/ethyl acetate) to give the titlecompound (17.30 mg, 0.037 mmol, 8.35%) as a pale yellow solid.

MS(API): Calculated 473.6, Found 474.2 (M+H).

¹H NMR (300 MHz, CDCl₃): δ0.22-0.42 (9H, m), 1.70-2.10 (3H, m),3.28-3.64 (7H, m), 4.23-4.52 (3H, m), 5.56-5.86 (2H, m), 7.07-7.38 (5H,m), 7.44 (2H, d, J=7.9 Hz), 9.34 (1H, brs).

Example 34N-(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxyazetidine-1-carboxamide

A solution of azetidin-3-ol hydrochloride (240 mg, 2.19 mmol) and DIEA(1.146 mL, 6.56 mmol) in DMF (2 mL) was added to a solution of4-nitrophenyl((2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(230 mg, 0.44 mmol) in DMF (2.000 mL), and the mixture was stirredovernight at room temperature. To the reaction mixture were added waterand ethyl acetate, and the organic layer was separated. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 10→100%ethyl acetate/hexane, 0→15% MeOH/ethyl acetate) to give the titlecompound (60.8 mg, 0.132 mmol, 30.2%) as a white solid.

MS(API): Calculated 459.6, Found 460.3 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.11-0.41 (9H, m), 3.28 (3H, s), 3.53-3.75(2H, m), 3.95-4.13 (2H, m), 4.29-4.49 (3H, m), 5.47 (1H, d, J=8.3 Hz),5.56 (1H, d, J=6.0 Hz), 6.84 (1H, d, J=8.3 Hz), 7.19-7.38 (4H, m),7.38-7.60 (3H, m), 10.47 (1H, s).

Example 35N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)amino)acetamide

To a solution of2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(145 mg, 0.40 mmol), 2-(5-methyl-1,3,4-oxadiazol-2-yl)acetic acid (65.7mg, 0.46 mmol), HOBt (30.8 mg, 0.20 mmol) and TEA (0.168 mL, 1.21 mmol)in DMF (4 mL) was added WSC (94 mg, 0.60 mmol), and the mixture wasstirred overnight at room temperature. To the reaction mixture wereadded water and ethyl acetate, and the organic layer was separated. Theorganic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 10→100% ethylacetate/hexane) to give the title compound (159 mg, 0.329 mmol, 82%) aswhite crystals.

MS(API): Calculated 484.6, Found 485.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.14-0.48 (9H, m), 2.48 (3H, s), 3.18-3.31(3H, m), 3.89-4.17 (2H, m), 4.29-4.52 (2H, m), 5.52-5.78 (1H, m),7.21-7.42 (4H, m), 7.42-7.58 (3H, m), 9.05-9.33 (1H, m), 10.64 (1H,brs).

Example 36N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

To a solution of2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(150 mg, 0.42 mmol), 2-(6-oxopyrimidin-1(6H)-yl)acetic acid (73.7 mg,0.48 mmol), HOBt (31.9 mg, 0.21 mmol) and TEA (0.174 mL, 1.25 mmol) inDMF (4 mL) was added WSC (97 mg, 0.62 mmol), and the mixture was stirredovernight at room temperature. To the reaction mixture were added waterand ethyl acetate, and the organic layer was separated. The organiclayer was dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 10→100% ethyl acetate/hexane,0→15% MeOH/ethyl acetate) to give the title compound (128 mg, 0.258mmol, 62.0%) as white crystals.

MS(API): Calculated 496.6, Found 497.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 3.26 (3H, s), 4.39 (2H, s),4.72 (2H, s), 5.65 (1H, d, J=7.6 Hz), 6.38 (1H, d, J=6.4 Hz), 7.21-7.41(4H, m), 7.41-7.59 (3H, m), 7.91 (1H, d, J=6.4 Hz), 8.37 (1H, s), 9.26(1H, d, J=7.9 Hz), 10.61 (1H, s).

Example 37N-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide(Mixture of Four Optical Isomers)

(Step 1)

To a solution of 3,5-difluoro-4-(trimethylsilyl)aniline (1.0 g, 4.97mmol), 2-(diallylamino)-2-(4-methoxyphenyl)acetic acid (1.428 g, 5.46mmol), DMAP (0.668 g, 5.46 mmol) and DIEA (4.34 mL, 24.84 mmol) in ethylacetate (30 mL) was added T3P (4.38 mL, 7.45 mmol), and the mixture wasstirred at 80° C. for 2 hr. To the reaction mixture were added water andethyl acetate, and the organic layer was separated. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 5→20% ethylacetate/hexane) to give2-(diallylamino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(1.450 g, 3.26 mmol, 65.6%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ0.34 (9H, t, J=1.5 Hz), 2.88 (2H, dd, J=14.5,7.0 Hz), 3.23-3.39 (2H, m), 3.81 (3H, s), 4.49 (1H, s), 5.22 (2H, dd,J=6.6, 0.9 Hz), 5.27 (2H, s), 5.73-5.95 (2H, m), 6.85-6.95 (2H, m),7.04-7.15 (2H, m), 7.15-7.24 (2H, m), 9.53 (1H, s).

(Step 2)

A solution of2-(diallylamino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(1.45 g, 3.26 mmol), 1,3-dimethylbarbituric acid (1.069 g, 6.85 mmol)and Pd(PPh₃)₄ (0.151 g, 0.13 mmol) in THE (15 mL) was stirred overnightat room temperature under nitrogen atmosphere. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;5→75% ethyl acetate/hexane) to give2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(0.621 g, 1.703 mmol, 52.2%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.33 (9H, t, J=1.3 Hz), 1.61 (2H, brs), 3.79(3H, s), 4.59 (1H, s), 6.83-6.93 (2H, m), 7.07-7.18 (2H, m), 7.28-7.37(2H, m), 9.53 (1H, brs).

(Step 3)

5-Oxopyrrolidine-3-carboxylic acid (53.1 mg, 0.41 mmol), HATU (188 mg,0.49 mmol) and DIEA (0.144 mL, 0.82 mmol) were added to a solution of2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(150 mg, 0.41 mmol) in DMF (4 mL), and the mixture was stirred overnightat room temperature. To the reaction mixture were added water and ethylacetate, and the organic layer was separated. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→5% MeOH/ethylacetate) to give the title compound (125 mg, 0.263 mmol, 63.9%) as awhite solid.

MS(API): Calculated 475.6, Found 474.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 2.20-2.38 (2H, m), 3.09-3.29(1H, m), 3.34-3.51 (2H, m), 3.74 (3H, s), 5.47 (1H, t, J=6.8 Hz), 6.94(2H, dd, J=8.7, 1.1 Hz), 7.20 (2H, d, J=9.4 Hz), 7.37 (2H, d, J=9.1 Hz),7.54 (1H, d, J=3.4 Hz), 8.76 (1H, t, J=7.6 Hz), 10.65 (1H, d, J=3.8 Hz).

Example 38N-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

(Step 1)

To a solution of 3,5-difluoro-4-(trimethylsilyl)aniline (2.136 g, 10.61mmol), 2-(allyl(methyl)amino)-2-(4-(methoxymethyl)phenyl)acetic acid(2.91 g, 11.67 mmol), DMAP (1.426 g, 11.67 mmol) and DIEA (9.27 mL,53.06 mmol) in ethyl acetate (60 mL) was added T3P (9.36 mL, 15.92mmol), and the mixture was stirred at 80° C. for 4 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→35% ethyl acetate/hexane) to give2-(allyl(methyl)amino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(3.71 g, 8.58 mmol, 81%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.33 (9H, t, J=1.5 Hz), 2.20 (3H, s),2.88-3.15 (2H, m), 3.39 (3H, s), 4.18 (1H, s), 4.45 (2H, s), 5.15-5.33(2H, m), 5.78-5.96 (1H, m), 7.04-7.16 (2H, m), 7.31 (4H, q, J=8.3 Hz),9.37 (1H, s).

(Step 2)

A solution of2-(allyl(methyl)amino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(3.71 g, 8.58 mmol), 1,3-dimethylbarbituric acid (1.473 g, 9.43 mmol)and Pd(PPh₃)₄ (0.297 g, 0.26 mmol) in THF (40 mL) was stirred overnightat room temperature under nitrogen atmosphere. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;10-60% ethyl acetate/hexane) to giveN-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(methylamino)acetamide(3.16 g, 8.05 mmol, 94%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.33 (9H, t, J=1.3 Hz), 1.62 (1H, brs), 2.53(3H, s), 3.37 (3H, s), 4.13 (1H, s), 4.43 (2H, s), 7.03-7.18 (2H, m),7.28-7.41 (4H, m), 9.44 (1H, s).

(Step 3)

3-Hydroxy-1,2-oxazole-5-carboxylic acid (1.091 g, 8.45 mmol), HATU (3.67g, 9.66 mmol) and DIEA (2.81 mL, 16.10 mmol) were added to a solution ofN-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(methylamino)acetamide(3.16 g, 8.05 mmol) in DMF (50 mL), and the mixture was stirredovernight at 80° C. To the reaction mixture were added water and ethylacetate, and the organic layer was separated. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 30-100% ethylacetate/hexane) to give the title compound (2.96 g, 5.88 mmol, 73.0%) asa white solid.

MS(API): Calculated 503.6, Found 502.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.32 (9H, s), 2.70-2.97 (3H, m), 3.30 (3H,s), 4.43 (2H, s), 6.19 (1H, s), 6.57 (1H, s), 7.13-7.36 (4H, m),7.36-7.47 (2H, m), 10.80 (1H, s), 11.77 (1H, brs).

Example 39N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide

(Step 1)

n-BuLi (5.27 mL, 8.43 mmol) was added to a solution of diisopropylamine(1.301 mL, 9.20 mmol) in THF (40 mL) at −78° C. under argon gasatmosphere, and the mixture was stirred for 20 min. Then, a solution of3-(benzyloxy)-5-methyl-1,2-oxazole (1450 mg, 7.66 mmol) in THF (10.0 mL)was added thereto at −78° C., and the mixture was stirred for 50 min.Then, a solution of chloroethyl formate (0.875 mL, 9.20 mmol) in THF(5.0 mL) was added thereto at −78° C., and the mixture was stirred for 2hr. To the reaction mixture was added aqueous ammonium chloridesolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 5→20%ethyl acetate/hexane) to give diethyl2-(3-(benzyloxy)-1,2-oxazol-5-yl)malonate (391 mg, 1.173 mmol, 15.31%)as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ1.23-1.37 (6H, m), 4.19-4.33 (4H, m), 4.77(1H, s), 5.27 (2H, s), 6.14 (1H, s), 7.29-7.50 (5H, m).

(Step 2)

2N Aqueous sodium hydroxide solution (3.52 mL, 7.04 mmol) was added to asolution of diethyl 2-(3-(benzyloxy)-1,2-oxazol-5-yl)malonate (391 mg,1.17 mmol) in EtOH (3.5 mL), and the mixture was stirred at roomtemperature for 3 hr. THF (1.50 mL) was added thereto, and the mixturewas stirred at room temperature for 1 hr, and then overnight at 50° C.The reaction mixture was neutralized with 1N hydrochloric acid, andextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was crystallized from hexane/IPE to give2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetic acid (154 mg, 0.660 mmol, 56.3%)as a white solid.

¹H NMR (300 MHz, CDCl₃): δ3.79 (2H, s), 5.26 (2H, s), 5.97 (1H, s),7.30-7.50 (5H, m) (COOH D peak was not observed.).

(Step 3)

2-(3-(Benzyloxy)-1,2-oxazol-5-yl)acetic acid (154 mg, 0.66 mmol), HATU(301 mg, 0.79 mmol) and DIEA (0.231 mL, 1.32 mmol) were added to asolution of2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(275 mg, 0.73 mmol) in DMF (5 mL), and the mixture was stirred overnightat room temperature. To the reaction mixture were added water and ethylacetate, and the organic layer was separated. The organic layer waswashed with brine, and dried over sodium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 10→50% ethylacetate/hexane) to give2-(2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetamide)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(318 mg, 0.536 mmol, 81%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ0.31 (9H, s), 3.36 (3H, s), 3.72 (2H, s), 4.40(2H, s), 5.24 (2H, s), 5.68 (1H, d, J=6.0 Hz), 5.91 (1H, s), 6.85-7.00(2H, m), 7.17 (1H, brs), 7.28-7.47 (9H, m), 8.19 (1H, brs).

(Step 4)

A solution of2-(2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetamide)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(300 mg, 0.51 mmol) and 10-palladium-barium sulfate (53.8 mg, 0.051mmol) in MeOH (5 mL) was stirred at room temperature for 5 hr underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 50→100% ethyl acetate/hexane) to give the title compound (197mg, 0.391 mmol, 77%) as a white solid.

MS(API): Calculated 503.6, Found 504.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 3.28 (3H, s), 3.71 (2H, s),4.39 (2H, s), 5.57 (1H, d, J=7.2 Hz), 5.84 (1H, s), 7.14-7.28 (2H, m),7.28-7.39 (2H, m), 7.40-7.51 (2H, m), 9.05 (1H, d, J=7.6 Hz), 10.75 (1H,s), 11.13 (1H, brs).

Example 40N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

2-(6-Oxopyrimidin-1(6H)-yl)acetic acid (55.0 mg, 0.36 mmol), HATU (163mg, 0.43 mmol) and DIEA (0.125 mL, 0.71 mmol) were added to a solutionof2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(135 mg, 0.36 mmol) in DMF (4 mL), and the mixture was stirred overnightat room temperature. To the reaction mixture were added water and ethylacetate, and the organic layer was separated. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→51% MeOH/ethylacetate) to give the title compound (100 mg, 0.194 mmol, 54.5%) as awhite solid.

MS(API): Calculated 514.6, Found 513.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 3.25-3.30 (3H, m), 4.40 (2H,s), 4.72 (2H, s), 5.55-5.66 (1H, m), 6.38 (1H, d, J=6.4 Hz), 7.13-7.27(2H, m), 7.29-7.39 (2H, m), 7.41-7.53 (2H, m), 7.91 (1H, d, J=6.4 Hz),8.37 (1H, s), 9.27 (1H, d, J=7.6 Hz), 10.75 (1H, s).

Example 41N-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxyazetidine-1-carboxamide

A solution of pyridine (0.048 mL, 0.59 mmol) and2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(108 mg, 0.30 mmol) in THF (2 mL) was added to a solution ofbis(trichloromethyl) carbonate (34.3 mg, 0.12 mmol) in THF (2 mL) at 0°C., and the mixture was stirred at 0° C. for 15 min. Then, a solution ofazetidin-3-ol hydrochloride (97 mg, 0.89 mmol) and DIEA (0.155 mL, 0.89mmol) in DMF (1 mL) was added thereto at 0° C., and the mixture wasstirred overnight at room temperature. To the reaction mixture wereadded water and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 30-100% ethyl acetate/hexane) to give the title compound(16.30 mg, 0.035 mmol, 11.87%) as a white solid.

MS(API): Calculated 463.6, Found 464.1 (M+H).

¹H NMR (300 MHz, CDCl₃): δ0.30 (9H, s), 2.88 (1H, brs), 3.73 (3H, s),3.90 (2H, td, J=9.3, 4.2 Hz), 4.24 (2H, q, J=6.9 Hz), 4.63 (1H, brs),5.49 (1H, d, J=7.2 Hz), 5.66 (1H, d, J=7.6 Hz), 6.79 (2H, d, J=8.3 Hz),6.99 (2H, d, J=9.1 Hz), 7.33 (2H, d, J=8.3 Hz), 9.45 (1H, brs).

Example 42N-(2-((2,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide(Mixture of Four Optical Isomers)

(Step 1)

To a solution of 2-(diallylamino)-2-(4-methoxyphenyl)acetic acid (4.70g, 18.00 mmol), 2,5-difluoro-4-(trimethylsilyl)aniline (3.019 g, 15.00mmol), DIEA (13.06 mL, 74.99 mmol) and DMAP (2.016 g, 16.50 mmol) inethyl acetate (100 mL) was added T3P (13.38 mL, 22.50 mmol), and themixture was stirred at 70° C. for 15 hr. To the reaction mixture wereadded aqueous sodium hydrogencarbonate solution and ethyl acetate, andthe organic layer was separated. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (NH, solvent gradient; 2→5% ethyl acetate/hexane)to give2-(diallylamino)-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(3.09 g) as a pale yellow oil.

(Step 2)

A solution of2-(diallylamino)-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(3.09 g), Pd(PPh₃)₄ (321 mg, 0.28 mmol) and 1,3-dimethylbarbituric acid(2.39 g, 15.31 mmol) in THF (65 mL) was stirred at room temperature for15 hr under argon gas atmosphere, and the mixture was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (NH, solvent gradient; 5→50% ethyl acetate/hexane) togive2-amino-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(1.02 g, 2.80 mmol, 18.66%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.28 (9H, s), 1.95 (2H, s), 3.79 (3H, s), 4.63(1H, s), 6.89 (2H, d, J=9.1 Hz), 7.05 (1H, dd, J=10.6, 4.5 Hz), 7.35(2H, d, J=8.7 Hz), 8.10 (1H, dd, J=9.6, 5.9 Hz), 9.80 (1H, brs).

(Step 3)

To a solution of2-amino-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(200 mg, 0.55 mmol), 5-oxopyrrolidine-3-carboxylic acid (78 mg, 0.60mmol) and DIEA (191 μL, 1.10 mmol) in DMF (3 mL) was added HATU (250 mg,0.66 mmol), and the mixture was stirred at room temperature for 15 hr.To the reaction mixture were added water and ethyl acetate, and theorganic layer was separated. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→5% MeOH/ethyl acetate) to give thetitle compound (187.8 mg, 0.395 mmol, 72.0%) as a white solid.

MS(API): Calculated 475.6, Found 474.1 (M−H).

¹H NMR (300 MHz, CDCl₃): δ0.27 (9H, d, J=0.8 Hz), 2.44-2.75 (2H, m),3.23-3.35 (1H, m), 3.52-3.57 (1H, m), 3.60-3.67 (1H, m), 3.76-3.82 (3H,m), 5.59-5.66 (2H, m), 6.85-7.03 (4H, m), 7.34 (2H, d, J=8.7 Hz), 7.71(1H, brs), 7.95 (1H, dd, J=9.4, 6.0 Hz).

Example 43N-(2-((2,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

(Step 1)

To a solution of2-(allyl(methyl)amino)-2-(4-(methoxymethyl)phenyl)acetic acid (2.112 g,8.47 mmol), 2,5-difluoro-4-(trimethylsilyl)aniline (1.55 g, 7.70 mmol),DIEA (6.71 mL, 38.50 mmol) and DMAP (1.035 g, 8.47 mmol) in ethylacetate (50 mL) was added T3P (6.87 mL, 11.55 mmol), and the mixture wasstirred at 70° C. for 15 hr. To the reaction mixture were added aqueoussodium hydrogencarbonate solution and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (NH, solvent gradient; 2-5% ethyl acetate/hexane) to give2-(allyl(methyl)amino)-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(2.36 g) as a pale yellow oil.

(Step 2)

A solution of2-(allyl(methyl)amino)-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(2.36 g), Pd(PPh₃)₄(126 mg, 0.11 mmol) and 1,3-dimethylbarbituric acid(937 mg, 6.00 mmol) in THF (26 mL) was stirred at room temperature for15 hr under argon gas atmosphere, and the mixture was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (NH, solvent gradient; 3→30% ethyl acetate/hexane) togiveN-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(methylamino)acetamide(1.89 g, 4.82 mmol, 62.5%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.28 (9H, d, J=0.8 Hz), 1.75 (1H, s), 2.55(3H, s), 3.37 (3H, s), 4.17 (1H, s), 4.43 (2H, s), 7.0 (1H, dd, J=10.2,4.5 Hz), 7.32 (2H, d), 7.40 (2H, d), 8.07 (1H, dd, J=9.6, 5.9 Hz), 9.73(1H, brs).

(Step 3)

To a solution ofN-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(methylamino)acetamide(300 mg, 0.76 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (109 mg,0.84 mmol) and DIEA (266 μL, 1.53 mmol) in DMF (4 mL) was added HATU(349 mg, 0.92 mmol), and the mixture was stirred at room temperature for15 hr. To the reaction mixture were added water and ethyl acetate, andthe organic layer was separated. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 30→100% ethyl acetate/hexane),and crystallized from hexane/IPE to give the title compound (170.6 mg,0.339 mmol, 44.3%) as a white solid.

MS(API): Calculated 503.6, Found 502.2 (M−H).

¹H NMR (300 MHz, CDCl₃): δ0.29 (9H, d, J=0.8 Hz), 1.65 (1H, brs), 3.09(3H, s), 3.43 (3H, s), 4.49 (2H, s), 6.35 (1H, s), 6.47 (1H, s), 7.02(1H, dd, J=10.6, 4.5 Hz), 7.42 (4H, s), 7.77 (1H, brs), 8.08 (1H, dd,J=9.4, 6.0 Hz).

Example 44N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)amino)acetamide

(Step 1)

To a solution of 2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid(4.96 g, 18.00 mmol), 2,5-difluoro-4-(trimethylsilyl)aniline (3.02 g, 15mmol), DIEA (13.06 mL, 75.00 mmol) and DMAP (2.016 g, 16.50 mmol) inethyl acetate (100 mL) was added T3P (13.38 mL, 22.50 mmol), and themixture was stirred at 70° C. for 15 hr. To the reaction mixture wereadded aqueous sodium hydrogencarbonate solution and ethyl acetate, andthe organic layer was separated. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (NH, solvent gradient; 2→5% ethyl acetate/hexane)to give2-(diallylamino)-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxymethylphenyl)acetamide(3.13 g) as a pale yellow oil.

(Step 2)

A solution of2-(diallylamino)-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxymethylphenyl)acetamide(3.13 g), Pd(PPh₃)₄(315 mg, 0.27 mmol) and 1,3-dimethylbarbituric acid(2.34 g, 14.99 mmol) in THE (65 mL) was stirred at room temperature for15 hr under argon gas atmosphere, and the mixture was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (NH, solvent gradient; 5→50% ethyl acetate/hexane) togive2-amino-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(1.08 g, 2.85 mmol, 19.02%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.28 (9H, d, J=0.8 Hz), 1.98 (2H, s), 3.37(3H, s), 4.44 (2H, s), 4.68 (1H, s), 7.05 (1H, dd, J=1.6, 4.5 Hz), 7.34(2H, d), 7.42 (2H, d), 8.09 (1H, dd, J=9.6, 5.9 Hz), 9.83 (1H, brs).

(Step 3)

To a solution of2-amino-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(221 mg, 0.58 mmol), 2-(5-methyl-1,3,4-oxadiazol-2-yl)acetic acid (87mg, 0.61 mmol) and DIEA (203 μL, 1.17 mmol) in DMF (3 mL) was added HATU(266 mg, 0.70 mmol), and the mixture was stirred at room temperature for15 hr. To the reaction mixture were added water and ethyl acetate, andthe organic layer was separated. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 30→100% ethyl acetate/hexane)to give the title compound (175.7 mg, 0.350 mmol, 59.9%) as a whitesolid.

MS(API): Calculated 502.6, Found 503.2 (M+H).

¹H NMR (300 MHz, CDCl₃): δ0.27 (9H, d, J=0.8 Hz), 2.52 (3H, s), 3.38(3H, s), 3.90 (2H, s), 4.44 (2H, s), 5.67 (1H, d, J=6.4 Hz), 6.99 (1H,dd, J=10.2, 4.5 Hz), 7.35 (2H, d), 7.43 (2H, d), 7.79 (1H, brs),7.94-8.04 (2H, m).

Example 45N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

To a solution of2-amino-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(200 mg, 0.53 mmol), 2-(6-oxopyrimidin-1(6H)-yl)acetic acid (86 mg, 0.55mmol) and DIEA (184 μL, 1.06 mmol) in DMF (2.6 mL) was added HATU (241mg, 0.63 mmol), and the mixture was stirred at room temperature for 15hr. To the reaction mixture were added water and ethyl acetate, and theorganic layer was separated. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 30→100% ethyl acetate/hexane), andcrystallized from IPE/hexane to give the title compound (178.6 mg, 0.347mmol, 65.7%) as a white solid.

MS(API): Calculated 514.6, Found 515.2 (M+H).

¹H NMR (300 MHz, CDCl₃): δ0.27 (9H, d, J=0.8 Hz), 3.38 (3H, s), 4.42(2H, s), 4.56 (1H, d), 4.70 (1H, d), 5.61 (1H, d, J=6.8 Hz), 6.50 (1H,dd, J=6.4, 0.8 Hz), 6.98 (1H, dd, J=10.2, 4.5 Hz), 7.33 (2H, d), 7.38(2H, d), 7.70 (1H, d, J=6.4 Hz), 7.82 (1H, brs), 7.90-7.97 (2H, m), 8.13(1H, s).

Example 46N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-((1H-indazol-1-ylacetyl)amino)-2-(4-methoxyphenyl)acetamide

To a solution of2-amino-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(173 mg, 0.47 mmol), 2-(1H-indazol-1-yl)acetic acid (92 mg, 0.52 mmol)and DIEA (165 μL, 0.95 mmol) in DMF (2.4 mL) was added HATU (217 mg,0.57 mmol), and the mixture was stirred at room temperature for 15 hr.To the reaction mixture were added water and ethyl acetate, and theorganic layer was separated. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 8→50% ethyl acetate/hexane), andcrystallized from IPE/hexane to give the title compound (146.4 mg, 0.280mmol, 59.0%) as a white solid.

MS(API): Calculated 522.6, Found 523.2 (M+H).

¹H NMR (300 MHz, CDCl₃): δ0.25 (9H, d, J=0.8 Hz), 3.77 (3H, s),5.03-5.17 (2H, m), 5.58 (1H, d, J=6.8 Hz), 6.82 (2H, d, J=8.7 Hz), 6.96(1H, dd, J=10.2, 4.5 Hz), 7.18 (2H, d, J=8.7 Hz), 7.21-7.30 (2H, m),7.36-7.47 (2H, m), 7.74 (1H, brs), 7.79 (1H, d, J=7.9 Hz), 7.90 (1H, dd,J=9.6, 5.9 Hz), 8.18 (1H, d, J=0.8 Hz).

Example 47N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-((1H-indazol-1-ylacetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide

To a solution of2-amino-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(180 mg, 0.48 mmol), 2-(1H-indazol-1-yl)acetic acid (92 mg, 0.52 mmol)and DIEA (166 μL, 0.95 mmol) in DMF (2.4 mL) was added HATU (217 mg,0.57 mmol), and the mixture was stirred at room temperature for 15 hr.To the reaction mixture were added water and ethyl acetate, and theorganic layer was separated. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate), and crystallized fromIPE/hexane to give the title compound (220.6 mg, 0.411 mmol, 86%) as awhite solid.

MS(API): Calculated 536.6, Found 537.2 (M+H).

¹H NMR (300 MHz, CDCl₃): δ0.25 (9H, s), 3.36 (3H, s), 4.41 (2H, s),5.04-5.18 (2H, m), 5.59 (1H, d, J=6.4 Hz), 6.96 (1H, dd, J=10.2, 4.5Hz), 7.19-7.47 (8H, m), 7.67 (1H, brs), 7.79 (1H, d, J=8.3 Hz), 7.89(1H, dd, J=9.4, 5.7 Hz), 8.19 (1H, s).

Example 48N-(2-((3-chloro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

(Step 1)

Microflow system consisting of two T-type micromixers (M1, M2), twomicrotube reactors (R1, R2) and three tube precooling units (P1 (innerdiameter φ=1 mm, length L=100 cm), P2 (φ=1 mm, L=50 cm) and P3 (φ=1 mm,L=100 cm)) was cooled to −20° C. A solution (flow rate: 6.0 mL/min) of2-chloro-1-iodo-4-nitrobenzene (2835 mg, 10 mmol) in THF (100 mL) and0.4M phenyllithium in dibutyl ether and THF mixed solution (100 mL,40.00 mmol) (flow rate: 2.25 mL/min) were introduced into M1 (φ=0.5 mm)using syringe pump. The reaction solution was passed through R1 (φ=1 mm,L=25 cm), and 0.6M chlorotrimethylsilane THF solution (100 mL, 60.00mmol) (flow rate: 3.0 mL/min) was mixed in M2 (φ=1 mm). The reactionsolution was passed through R2 (φ=1 nm, L=100 cm). After the reactionreached the static state, the solution containing a product was pouredinto water. The mixture was extracted with ethyl acetate, the organiclayer was dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 0→5% ethyl acetate/hexane) togive (2-chloro-4-nitrophenyl)trimethylsilane (780 mg, 3.40 mmol, 34.0%)as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ0.40 (9H, s), 7.78 (1H, d, J=8.3 Hz),8.13-8.17 (1H, m), 8.20 (1H, d, J=2.3 Hz).

(Step 2)

A solution of (2-chloro-4-nitrophenyl)trimethylsilane (0.30 g, 1.31mmol), calcium chloride (0.072 g, 0.65 mmol) and iron (0.365 g, 6.53mmol) in a mixed solvent of EtOH (10.88 mL) and water (2.176 mL) wasstirred at 100° C. for 2 hr. The insoluble substance was removed byfiltration, and the filtrate was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(solvent gradient; 0→15% ethyl acetate/hexane) to give3-chloro-4-(trimethylsilyl)aniline (0.150 g, 0.751 mmol, 57.5-) as apale yellow oil.

¹H NMR (300 MHz, DMSO-d₆) δ: 0.25 (9H, s), 5.51 (2H, s), 6.48 (1H, dd,J=8.1, 2.1 Hz), 6.58 (1H, d, J=2.3 Hz), 7.07 (1H, d, J=7.9 Hz).

(Step 3)

To a solution of 3-chloro-4-(trimethylsilyl)aniline (0.15 g, 0.75 mmol),2-(3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide)-2-(4-methoxyphenyl)aceticacid (0.253 g, 0.83 mmol), DMAP (0.101 g, 0.83 mmol) and DIEA (0.654 mL,3.75 mmol) in ethyl acetate (4.13 mL) was added T3P (0.663 mL, 1.13mmol), and the mixture was stirred at 80° C. for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→10% MeOH/ethyl acetate), and thenpreparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1,TFA)) to give the title compound (0.050 g, 0.102 mmol, 13.64%) as a paleyellow solid.

MS(API): Calculated 488.0, Found 486.1 (M−H).

Example 49(3S)—N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

(Step 1)

To a solution of2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(6.62 g, 18.36 mmol) and DIEA (9.62 mL, 55.09 mmol) in THF (130 mL) wasadded allyl chloroformate (2.338 mL, 22.04 mmol), and the mixture wasstirred at room temperature for 1 hr. To the reaction mixture were addedwater and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0→-10% ethyl acetate/hexane) to give allyl(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(5.08 g, 11.43 mmol, 62.2%) as a white solid.

(Step 2)

Allyl(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(6.955 g) was subjected to optical resolution using chiral columnchromatography. The preparative fraction having a shorter retention timewas concentrated to give allyl((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(2.16 g, >99.9% ee) as a white solid.

purification condition using chiral column chromatography

column: CHIRALCEL OD-H(OF002)30 mmID×250 mmL

solvent: CO₂/MeOH=860/140

back pressure: 100 bar

temperature: 35° C.

detection method: UV 220 nm

(Step 3)

A solution of allyl((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(340 mg, 0.76 mmol), 1,3-dimethylbarbituric acid (251 mg, 1.61 mmol) andPd(PPh₃)₄(35.4 mg, 0.03 mmol) in THF (6.0 mL) was stirred at roomtemperature for 2 hr under argon gas atmosphere. The reaction mixturewas concentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;5→50% ethyl acetate/hexane) to give(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(253.3 mg, 0.703 mmol, 92%) as a pale yellow oil.

(Step 4)

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(120 mg, 0.33 mmol), (S)-5-oxopyrrolidine-3-carboxylic acid (47.3 mg,0.37 mmol), DIEA (0.116 mL, 0.67 mmol) and HATU (152 mg, 0.40 mmol) inDMF (2.0 mL) was stirred at room temperature for 2 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate), and crystallized from ethylacetate/hexane to give the title compound (85.2 mg, 0.181 mmol, 54.3%)as white crystals.

MS(API): Calculated 471.6, Found 470.2 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.20-0.32 (9H, m), 2.23-2.37 (2H, m),3.11-3.21 (1H, m), 3.27 (3H, s), 3.35-3.47 (2H, m), 4.38 (2H, s), 5.61(1H, d, J=7.6 Hz), 7.23-7.39 (4H, m), 7.40-7.57 (4H, m), 8.83 (1H, d,J=7.6 Hz), 10.58 (1H, s).

[α]_(D) ²⁵−119.3 (c 0.1965, MeOH)

Example 50(3S)—N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

(Step 1)

To a solution of2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(7.78 g, 22.45 mmol) and DIEA (11.77 mL, 67.36 mmol) in THF (100 mL) wasadded allyl chloroformate (2.86 mL, 26.95 mmol) at 0° C., and themixture was stirred for 1 hr. To the reaction mixture were added waterand ethyl acetate, and the organic layer was separated. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 5→75%ethyl acetate/hexane), and crystallized from IPE/hexane to give allyl(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)carbamate(7.0 g, 16.26 mmol, 72.4%) as a white solid.

(Step 2)

Allyl(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)carbamate(7.0 g) was subjected to optical resolution using chiral columnchromatography. The preparative fraction having a shorter retention timewas concentrated to give allyl((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(3.383 g, >99.9% ee) as a white solid.

purification condition using chiral column chromatography

column: CHIRALPAK AD(NF001) 50 mmID×500 mmL

solvent: hexane/2-propanol=800/200

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

A solution of allyl((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(165 mg, 0.38 mmol), 1,3-dimethylbarbituric acid (132 mg, 0.84 mmol) andPd(PPh₃)₄ (17.71 mg, 0.02 mmol) in THE (2.55 mL) was stirred at roomtemperature for 6 hr under argon gas atmosphere. The reaction mixturewas concentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;40→80% ethyl acetate/hexane) to give(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(178 mg, 0.514 mmol, 134%) as a yellow oil.

(Step 4)

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(178 mg, 0.51 mmol), (S)-5-oxopyrrolidine-3-carboxylic acid (86 mg, 0.67mmol), HATU (293 mg, 0.77 mmol) and DIEA (0.269 mL, 1.54 mmol) in DMF(0.5 mL) was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→7% MeOH/ethyl acetate) to give thetitle compound (137 mg, 0.299 mmol, 58.3%) as a white solid.

MS(API): Calculated 457.6, Found 458.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 2.31 (2H, d, J=7.9 Hz), 3.17(1H, d, J=4.9 Hz), 3.33-3.44 (2H, m), 3.73 (3H, s), 5.53 (1H, d, J=7.6Hz), 6.94 (2H, d, J=8.7 Hz), 7.22-7.60 (6H, m), 8.76 (1H, d, J=7.2 Hz),10.51 (1H, s).

[α]_(D) ²⁵−107.9 (c 0.119, MeOH)

Example 51(3S)—N-((1R)-2-((2,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

(Step 1)

To a solution of2-amino-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(1.57 g, 4.15 mmol) and DIEA (2.173 mL, 12.44 mmol) in THF (30 mL) wasadded allyl chloroformate (0.528 mL, 4.98 mmol), and the mixture wasstirred at room temperature for 1 hr. To the reaction mixture were addedwater and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0→10% ethyl acetate/hexane) to give allyl(2-((2,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(2.59 g, 5.60 mmol, 135%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ0.27 (9H, d, J=0.8 Hz), 3.38 (3H, s), 4.45(2H, s), 4.54-4.61 (2H, m), 5.15-5.44 (3H, m), 5.80-6.03 (2H, m), 7.00(1H, dd, J=10.2, 4.5 Hz), 7.31-7.46 (4H, m), 7.69 (1H, brs), 7.99 (1H,dd, J=9.4, 5.7 Hz).

(Step 2)

Allyl(2-((2,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(1.37 g) was subjected to optical resolution using chiral columnchromatography. The preparative fraction having a shorter retention timewas concentrated to give allyl((1R)2-((2,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate (600.7 mg, >99.9% ee) as a white solid.

purification condition using chiral column chromatography

column: CHIRALPAK AD(LF001)50 mmID×500 mmL

solvent: hexane/EtOH=500/500

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 3)

A solution of allyl((1R)2-((2,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(600 mg, 1.30 mmol), 1,3-dimethylbarbituric acid (425 mg, 2.72 mmol) andPd(PPh₃)₄ (60.0 mg, 0.05 mmol) in THF (12 mL) was stirred at roomtemperature for 1 hr under argon gas atmosphere. The reaction mixturewas concentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;5→50% ethyl acetate/hexane) to give(R)-2-amino-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(524.8 mg, 1.387 mmol, 107%) as a yellow oil.

(Step 4)

A solution of(R)-2-amino-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.26 mmol), (S)-5-oxopyrrolidine-3-carboxylic acid (37.5 mg,0.29 mmol), DIEA (0.092 mL, 0.53 mmol) and HATU (121 mg, 0.32 mmol) inDMF (2.0 mL) was stirred at room temperature for 2 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate), and crystallized from ethylacetate/hexane to give the title compound (66.3 mg, 0.135 mmol, 51.3%)as white crystals.

MS(API): Calculated 489.6, Found 490.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.27 (9H, d, J=0.8 Hz), 2.26-2.35 (2H, m),3.10-3.23 (1H, m), 3.27 (3H, s), 3.36-3.45 (2H, m), 4.39 (2H, s), 5.85(1H, d, J=7.6 Hz), 7.20 (1H, dd, J=10.4, 4.7 Hz), 7.32 (2H, d, J=8.3Hz), 7.46 (2H, d, J=8.3 Hz), 7.53 (1H, s), 7.76 (1H, dd, J=10.4, 5.9Hz), 8.79 (1H, d, J=7.6 Hz), 10.36 (1H, s).

[α]_(D) ²⁵−112.6 (c 0.251, MeOH)

Example 52(3S)—N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

(Step 1)

To a solution of 3,5-difluoro-4-(trimethylsilyl)aniline (6.69 g, 33.25mmol), 2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid (11.9 g,43.22 mmol), DMAP (4.47 g, 36.57 mmol) and DIEA (29.0 mL, 166.23 mmol)in ethyl acetate (200 mL) was added T3P (29.3 mL, 49.87 mmol), and themixture was stirred at 80° C. for 1 hr. To the reaction mixture wereadded water and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 3→35% ethyl acetate/hexane) to give2-(diallylamino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(9.00 g, 19.62 mmol, 59.0%) as a pale yellow oil.

(Step 2)

A solution of2-(diallylamino)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(1.64 g, 3.58 mmol), 1,3-dimethylbarbituric acid (1.173 g, 7.51 mmol)and Pd(PPh₃)₄ (0.165 g, 0.14 mmol) in THF (15 mL) was stirred overnightat room temperature under argon gas atmosphere. The obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;5→75% ethyl acetate/hexane) to give2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(470.5 mg, 1.243 mmol, 34.8%) as a pale yellow oil.

(Step 3)

To a solution of2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(470 mg, 1.24 mmol) and DIEA (0.651 mL, 3.73 mmol) in THF (10 mL) wasadded allyl chloroformate (0.158 mL, 1.49 mmol) at 0° C., and themixture was stirred for 1 hr. To the reaction mixture were added waterand ethyl acetate, and the organic layer was separated. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 0→10%ethyl acetate/hexane) to give allyl(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(297 mg, 0.641 mmol, 51.7%) as a white solid.

(Step 4)

Allyl(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(296 mg) was subjected to optical resolution using chiral columnchromatography. The preparative fraction having a shorter retention timewas concentrated to give allyl(R)-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(108.5 mg, >99.9% ee) as a white solid.

purification condition using chiral column chromatography

column: CHIRALPAK AD(NF001) 50 mmID×500 mmL

solvent: hexane/EtOH=600/400

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 5)

A solution of allyl(R)-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(109 mg, 0.24 mmol), 1,3-dimethylbarbituric acid (81 mg, 0.52 mmol) andPd(PPh₃)₄(10.89 mg, 9.43 μmol) in THE (1571 μL) was stirred at roomtemperature for 6 hr under argon gas atmosphere. The reaction solutionwas concentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;40→80% ethyl acetate/hexane) to give(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.263 mmol, 112) as a yellow oil.

(Step 6)

A solution of(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(99.7 mg, 0.26 mmol), (S)-5-oxopyrrolidine-3-carboxylic acid (44.2 mg,0.34 mmol), HATU (150 mg, 0.40 mmol) and DIEA (0.138 mL, 0.79 mmol) inDMF (2 mL) was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 1→7% MeOH/ethyl acetate) to give(3S)—N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide(103 mg, 0.210 mmol, 80) as a white solid.

MS(API): Calculated 489.6, Found 488.2 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 2.26-2.34 (2H, m), 3.08-3.47(6H, m), 4.39 (2H, s), 5.57 (1H, d, J=7.6 Hz), 7.14-7.26 (2H, m),7.29-7.37 (2H, m), 7.39-7.47 (2H, m), 7.54 (1H, s), 8.85 (1H, d, J=7.2Hz), 10.73 (1H, s).

[α]_(D) ²⁵−103.2 (c 0.262, MeOH)

Example 53(2R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), 2-(6-oxopyrimidin-1(6H)-yl)acetic acid (47.0 mg,0.31 mmol), HATU (148 mg, 0.39 mmol) and DIEA (0.097 mL, 0.55 mmol) inDMF (2 mL) was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 1→7% MeOH/ethyl acetate), andcrystallized from ethyl acetate/hexane to give the title compound (68.1mg, 0.137 mmol, 49.4) as a white solid.

MS(API): Calculated 496.6, Found 497.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.17-0.33 (9H, m), 3.27 (3H, s), 4.39 (2H,s), 4.72 (2H, s), 5.65 (1H, d, J=7.6 Hz), 6.38 (1H, dd, J=6.8, 0.8 Hz),7.24-7.40 (4H, m), 7.43-7.54 (3H, m), 7.91 (1H, d, J=6.8 Hz), 8.37 (1H,s), 9.26 (1H, d, J=7.9 Hz), 10.62 (1H, s).

[α]_(D) ²⁵−49.8 (c 0.2515, MeOH)

Example 54(3R)—N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

(Step 1)

2-Methylenesuccinic acid (11.74 g, 90.24 mmol) and(R)-1-phenylethanamine (10.94 g, 90.24 mmol) were stirred at 160° C. for4 hr. The reaction mixture was crystallized from EtOH (50 mL)/water (50mL), and the obtained crystals were recrystallized from EtOH (70mL)/water (100 mL) to give(3R)-5-oxo-1-((1R)-1-phenylethyl)pyrrolidine-3-carboxylic acid (5.55 g,23.79 mmol, 52.9%) as pale orange crystals.

(Step 2)

A solution of (3R)-5-oxo-1-((1R)-1-phenylethyl)pyrrolidine-3-carboxylicacid (5.55 g, 23.79 mmol) in TFA (10 mL) was stirred under microwaveirradiation at 160° C. for 1.5 hr. Then, TEA (2 mL) was added thereto,and the mixture was stirred under microwave irradiation at 160° C. for0.5 hr. The reaction mixture was concentrated under reduced pressure,and the residue was crystallized from ethyl acetate to give(R)-5-oxopyrrolidine-3-carboxylic acid (2.1 g, 16.26 mmol, 68.4%) aswhite crystals.

(Step 3)

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), (R)-5-oxopyrrolidine-3-carboxylic acid (39.4 mg,0.31 mmol), HATU (148 mg, 0.39 mmol) and DIEA (0.097 mL, 0.55 mmol) inDMF (2 mL) was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 1-7% MeOH/ethyl acetate), andcrystallized from ethyl acetate/hexane to give the title compound (102mg, 0.216 mmol, 78%) as a white solid.

MS(API): Calculated 471.6, Found 470.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 2.22-2.30 (2H, m), 3.13-3.52(6H, m), 4.38 (2H, s), 5.59 (1H, d, J=7.6 Hz), 7.23-7.62 (8H, m), 8.80(1H, d, J=7.6 Hz), 10.57 (1H, s).

[α]_(D) ²⁵−85.0 (c 0.2595, MeOH)

Example 55(3R)—N-((1R)-2-((2,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

A solution of(R)-2-amino-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.26 mmol), (R)-5-oxopyrrolidine-3-carboxylic acid (37.5 mg,0.29 mmol), DIEA (0.092 mL, 0.53 mmol) and HATU (121 mg, 0.32 mmol) inDMF (2.0 mL) was stirred at room temperature for 2 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate), and crystallized from ethylacetate/hexane to give the title compound (62.9 mg, 0.128 mmol, 48.6%)as white crystals.

MS(API): Calculated 489.6, Found 488.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.26 (9H, d, J=0.8 Hz), 2.21-2.30 (2H, m),3.21-3.28 (4H, m), 3.37-3.49 (2H, m), 4.39 (2H, s), 5.83 (1H, d, J=7.2Hz), 7.20 (1H, dd, J=10.6, 4.9 Hz), 7.32 (2H, d, J=7.9 Hz), 7.46 (2H, d,J=7.9 Hz), 7.55 (1H, s), 7.77 (1H, dd, J=10.6, 5.7 Hz), 8.76 (1H, d,J=7.2 Hz), 10.35 (1H, s).

Example 56(2R)—N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)amino)acetamide

A solution of(R)-2-amino-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(200 mg, 0.53 mmol), 2-(5-methyl-1,3,4-oxadiazol-2-yl)acetic acid (83mg, 0.58 mmol), DIEA (0.185 mL, 1.06 mmol) and HATU (241 mg, 0.63 mmol)in DMF (2.0 mL) was stirred at room temperature for 2 hr. To thereaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (110.2mg, 0.219 mmol, 41.5%) as white crystals.

MS(API): Calculated 502.6, Found 503.2 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.27 (9H, d, J=0.8 Hz), 2.46 (3H, s), 3.28(3H, s), 3.98 (2H, s), 4.40 (2H, s), 5.87 (1H, d, J=7.2 Hz), 7.20 (1H,dd, J=10.4, 4.7 Hz), 7.33 (2H, d, J=8.3 Hz), 7.49 (2H, d, J=8.3 Hz),7.76 (1H, dd, J=10.4, 5.9 Hz), 9.14 (1H, d, J=7.2 Hz), 10.42 (1H, s).

Example 57(2R)—N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

A solution of(R)-2-amino-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(150 mg, 0.40 mmol), 2-(6-oxopyrimidin-1(6H)-yl)acetic acid (61.1 mg,0.40 mmol), DIEA (0.138 mL, 0.79 mmol) and HATU (181 mg, 0.48 mmol) inDMF (2.0 ML) was stirred at room temperature for 2 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (102.5mg, 0.199 mmol, 50.3%) as white crystals.

MS(API): Calculated 514.6, Found 515.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.27 (9H, d, J=0.8 Hz), 3.28 (3H, s), 4.40(2H, s), 4.71 (2H, s), 5.91 (1H, d, J=7.6 Hz), 6.38 (1H, dd, J=6.4, 0.8Hz), 7.20 (1H, dd, J=10.6, 4.9 Hz), 7.33 (2H, d, J=8.3 Hz), 7.49 (2H, d,J=8.3 Hz), 7.77 (1H, dd, J=10.6, 5.9 Hz), 7.91 (1H, d, J=6.4 Hz), 8.37(1H, s), 9.21 (1H, d, J=7.6 Hz), 10.43 (1H, s).

Example 58(2R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

A solution of(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.26 mmol), 2-(6-oxopyrimidin-1(6H)-yl)acetic acid (44.8 mg,0.29 mmol), HATU (111 mg, 0.29 mmol) and DIEA (0.051 mL, 0.29 mmol) inDMF (2 mL) was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 20→100% ethyl acetate/hexane), andcrystallized from acetone/water to give the title compound (80 mg, 0.155mmol, 58.8%) as white crystals.

MS(API): Calculated 514.6, Found 513.1 (M−H). 1H NMR (300 MHz, DMSO-d₆):δ0.30 (9H, s), 3.28 (3H, s), 4.40 (2H, s), 4.72 (2H, s), 5.61 (1H, d,J=7.2 Hz), 6.39 (1H, d, J=7.2 Hz), 7.21 (2H, d, J=9.4 Hz), 7.29-7.38(2H, m), 7.41-7.52 (2H, m), 7.91 (1H, d, J=6.4 Hz), 8.37 (1H, s), 9.27(1H, d, J=7.6 Hz), 10.75 (1H, s).

[α]_(D) ²⁵−48.5 (c 0.2600, MeOH)

Example 59(2R)-2-(((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)amino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), 2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)aceticacid (51.9 mg, 0.31 mmol), DIEA (0.097 mL, 0.55 mmol) and HATU (127 mg,0.33 mmol) in DMF (2.0 mL) was stirred at room temperature for 2 hr. Tothe reaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 20→100% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (77.0mg, 0.150 mmol, 54.2%) as a white solid. MS(API): Calculated 512.6,Found 513.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 3.27 (3H, s), 4.39 (2H, s),4.48 (2H, s), 5.54 (1H, d, J=7.9 Hz), 5.65 (1H, d, J=7.9 Hz), 7.24-7.39(4H, m), 7.42-7.59 (4H, m), 9.11 (1H, d, J=7.9 Hz), 10.61 (1H, s), 11.26(1H, s).

[α]_(D) ²⁵−57.2 (c 0.2515, MeOH)

Example 60 (2R)-2-(((2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)acetyl)amino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), 2-(2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)aceticacid (51.9 mg, 0.31 mmol), DIEA (0.097 mL, 0.55 mmol) and HATU (127 mg,0.33 mmol) in DMF (2.0 mL) was stirred at room temperature for 2 hr. Tothe reaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate), and crystallized from ethylacetate/hexane to give the title compound (24.8 mg, 0.048 mmol, 17.44%)as a white solid.

MS(API): Calculated 512.6, Found 513.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 3.27 (3H, s), 4.39 (2H, s),4.48 (2H, s), 5.54 (1H, d, J=7.9 Hz), 5.62-5.67 (1H, m), 7.25-7.36 (4H,m), 7.41-7.59 (4H, m), 9.11 (1H, d, J=7.9 Hz), 10.61 (1H, s), 11.25 (1H,brs).

[α]_(D) ²⁵−55.6 (c 0.2505, MeOH)

Example 61(2R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((3-methyl-6-oxopyridazin-1(6H)-yl)acetyl)amino)acetamide

A solution of(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(60 mg, 0.16 mmol), 2-(3-methyl-6-oxopyridazin-1(6H)-yl)acetic acid(29.3 mg, 0.17 mmol), DIEA (0.055 mL, 0.32 mmol) and HATU (72.3 mg, 0.19mmol) in DMF (2.0 mL) was stirred at room temperature for 2 hr. To thereaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (56.7mg, 0.107 mmol, 67.7%) as a white solid.

MS(API): Calculated 512.6, Found 529.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.28-0.33 (9H, m), 2.24 (3H, s), 3.28 (3H,s), 4.40 (2H, s), 4.76 (2H, s), 5.57 (1H, d, J=7.2 Hz), 6.88 (1H, d,J=9.8 Hz), 7.23 (2H, d, J=9.8 Hz), 7.31-7.38 (3H, m), 7.42-7.49 (2H, m),9.08 (1H, d, J=7.2 Hz), 10.72 (1H, s).

[α]_(D) ²⁵−546.8 (c 0.2495, MeOH)

Example 62 (2R)-2-(((2,5-dioxoimidazolidin-1-yl)acetyl)amino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), 2-(2,5-dioxoimidazolidin-1-yl)acetic acid (48.2 mg,0.31 mmol), DIEA (0.097 mL, 0.55 mmol) and HATU (127 mg, 0.33 mmol) inDMF (2.0 mL) was stirred at room temperature for 2 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate), and crystallized from ethylacetate/hexane to give the title compound (72.3 mg, 0.144 mmol, 52.1%)as a white solid.

MS(API): Calculated 500.6, Found 501.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, d, J=0.8 Hz), 3.27 (3H, s), 3.95(2H, s), 4.10 (2H, d, J=1.9 Hz), 4.39 (2H, s), 5.61 (1H, d, J=7.6 Hz),7.26-7.38 (4H, m), 7.42-7.53 (3H, m), 8.09 (1H, s), 9.04 (1H, d, J=7.6Hz), 10.59 (1H, s).

[α]_(D) ²⁵−79.3 (c 0.2570, MeOH)

Example 63(2R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((4-oxopyridazin-1(4H)-yl)acetyl)amino)acetamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(140 mg, 0.39 mmol), 2-(4-oxopyridazin-1(4H)-yl)acetic acid (65.8 mg,0.43 mmol), HATU (207 mg, 0.54 mmol) and DIEA (0.136 mL, 0.78 mmol) inDMF (2 mL) was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 1→7% MeOH/ethyl acetate), andcrystallized from EtOH/hexane to give the title compound (48.0 mg, 0.097mmol, 24.89%) as white crystals.

MS(API): Calculated 496.6, Found 495.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, d, J=0.8 Hz), 3.31 (3H, s), 4.39(2H, s), 4.92 (2H, s), 5.59-5.71 (1H, m), 6.33 (1H, dd, J=7.7, 3.2 Hz),7.22-7.54 (7H, m), 7.72 (1H, d, J=3.0 Hz), 8.17 (1H, d, J=7.6 Hz), 9.23(1H, d, J=7.9 Hz), 10.64 (1H, s).

[α]_(D) ²⁵−97.4 (c 0.2455, MeOH)

Example 64(3S)—N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxypyrrolidine-1-carboxamide

A solution of bis(trichloromethyl) carbonate (100 mg, 0.34 mmol) in THF(6 mL) was added to a solution of pyridine (0.140 mL, 1.73 mmol) and(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(300 mg, 0.87 mmol) in THF (6 mL) at 0° C., and the mixture was stirredfor 10 min. To the reaction mixture was added a solution of(S)-(−)-3-hydroxypyrrolidine (0.180 mL, 2.16 mmol) in DMF (6 mL) at 0°C., and the mixture was stirred at room temperature for 1 hr. To thereaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 50→100% ethyl acetate/hexane, 0→10%MeOH/ethyl acetate), and crystallized from ethyl acetate/hexane to givethe title compound (26.6 mg, 0.058 mmol, 6.683) as white crystals.

MS(API): Calculated 459.6, Found 460.3 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 1.64-1.96 (2H, m), 3.16-3.26(1H, m), 3.33-3.45 (3H, m), 3.73 (3H, s), 4.24 (1H, brs), 4.89 (1H, d,J=3.4 Hz), 5.37-5.48 (1H, m), 6.31 (1H, d, J=7.9 Hz), 6.85-6.96 (2H, m),7.24-7.43 (4H, m), 7.51 (1H, dd, J=11.3, 1.5 Hz), 10.40 (1H, s).

Example 65(3S)—N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxypyrrolidine-1-carboxamide

A solution of bis(trichloromethyl) carbonate (96 mg, 0.32 mmol) in THF(2 mL) was added to a solution of pyridine (0.135 mL, 1.66 mmol) and(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(300 mg, 0.83 mmol) in THF (3 mL) at 0° C., and the mixture was stirredfor 10 min. To the reaction mixture was added a solution of(S)-(−)-3-hydroxypyrrolidine (0.173 mL, 2.08 mmol) in DMF (5 mL) at 0°C., and the mixture was stirred at room temperature for 1 hr. To thereaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→10% MeOH/ethyl acetate), andcrystallized from ethyl acetate/hexane to give the title compound (246mg, 0.519 mmol, 62.4%) as white crystals.

MS(API): Calculated 473.6, Found 474.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 1.68-1.94 (2H, m), 3.18-3.42(7H, m), 4.19-4.30 (1H, m), 4.38 (2H, s), 4.89 (1H, d, J=3.4 Hz), 5.50(1H, d, J=7.9 Hz), 6.41 (1H, d, J=7.9 Hz), 7.22-7.59 (7H, m), 10.46 (1H,s).

Example 66(3R)—N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxypyrrolidine-1-carboxamide

A solution of bis(trichloromethyl) carbonate (96 mg, 0.32 mmol) in THE(2 mL) was added to a solution of pyridine (0.135 mL, 1.66 mmol) and(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(300 mg, 0.83 mmol) in THF (3 mL) at 0° C., and the mixture was stirredfor 10 min. To the reaction mixture was added a solution of(R)-pyrrolidin-3-ol (0.173 mL, 2.08 mmol) in DMF (5 mL) at 0° C., andthe mixture was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→10% MeOH/ethyl acetate), andcrystallized from ethyl acetate/hexane to give the title compound (246mg, 0.519 mmol, 62.4%) as white crystals.

MS(API): Calculated 473.6, Found 474.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.21-0.29 (9H, m), 1.68-1.95 (2H, m),3.14-3.45 (7H, m), 4.25 (1H, brs), 4.38 (2H, s), 4.89 (1H, d, J=3.4 Hz),5.46-5.54 (1H, m), 6.41 (1H, d, J=8.3 Hz), 7.24-7.56 (7H, m), 10.47 (1H,s).

Example 67(2R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)amino)acetamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), 2-(5-methyl-1,3,4-oxadiazol-2-yl)acetic acid (43.4mg, 0.31 mmol), HATU (148 mg, 0.39 mmol) and DIEA (0.097 mL, 0.55 mmol)in DMF (2 mL) was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 1→7% MeOH/ethyl acetate), andcrystallized from EtOH/water to give the title compound (68.2 mg, 0.141mmol, 50.7%) as white crystals.

MS(API): Calculated 484.6, Found 483.2 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 2.46 (3H, s), 3.27 (3H, s),3.99 (2H, s), 4.39 (2H, s), 5.56-5.69 (1H, m), 7.23-7.54 (7H, m), 9.19(1H, d, J=7.6 Hz), 10.62 (1H, s).

Example 68(3R)—N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

A solution of(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.26 mmol), (R)-5-oxopyrrolidine-3-carboxylic acid (37.5 mg,0.29 mmol), HATU (111 mg, 0.29 mmol) and DIEA (37.6 mg, 0.29 mmol) inDMF (5 mL) was stirred at room temperature for 3 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→100% ethyl acetate/hexane), andcrystallized from acetone/water to give the title compound (45.0 mg,0.092 mmol, 34.83) as white crystals.

MS(API): Calculated 489.6, Found 488.2 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 1.04 (2H, d, J=6.0 Hz),2.18-2.35 (2H, m), 3.23-3.30 (4H, m), 4.39 (2H, s), 5.54 (1H, d, J=7.2Hz), 7.21 (2H, d, J=9.8 Hz), 7.28-7.38 (2H, m), 7.39-7.47 (2H, m), 7.55(1H, s), 8.82 (1H, d, J=7.6 Hz), 10.71 (1H, s).

Example 69N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxyazetidine-1-carboxamide

A solution of bis(trichloromethyl) carbonate (96 mg, 0.32 mmol) in THF(2 mL) was added to pyridine (0.135 mL, 1.66 mmol) and(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(300 mg, 0.83 mmol) in THE (3 mL) at 0° C., and the mixture was stirredfor 10 min. To the reaction mixture was added a solution ofazetidin-3-ol hydrochloride (228 mg, 2.08 mmol) in DMF (5 mL) at 0° C.,and the mixture was stirred at room temperature for 1 hr. To thereaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→10% MeOH/ethyl acetate), andcrystallized from ethyl acetate/hexane to give the title compound (8.8mg, 0.019 mmol, 2.301%) as white crystals.

MS(API): Calculated 459.6, Found 460.3 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, d, J=0.8 Hz), 3.26 (3H, s),3.57-3.66 (2H, m), 3.99-4.09 (2H, m), 4.37 (3H, s), 5.43-5.49 (1H, m),5.56 (1H, d, J=6.0 Hz), 6.84 (1H, d, J=7.9 Hz), 7.25-7.37 (4H, m),7.41-7.54 (3H, m), 10.47 (1H, s).

Example 70(3R)—N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(120 mg, 0.35 mmol), (R)-5-oxopyrrolidine-3-carboxylic acid (49.2 mg,0.38 mmol), DIEA (0.121 mL, 0.69 mmol) and HATU (158 mg, 0.42 mmol) inDMF (2.0 mL) was stirred at room temperature for 2 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate), and crystallized from ethylacetate/hexane to give the title compound (82.6 mg, 0.181 mmol, 52.1%)as a white solid.

MS(API): Calculated 457.6, Found 458.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, d, J=0.8 Hz), 2.20-2.32 (2H, m),3.21-3.28 (1H, m), 3.34-3.50 (2H, m), 3.73 (3H, s), 5.51 (1H, d, J=7.2Hz), 6.90-6.98 (2H, m), 7.23-7.42 (4H, m), 7.45-7.58 (2H, m), 8.73 (1H,d, J=7.2 Hz), 10.50 (1H, s).

Example 71(3R)—N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxypyrrolidine-1-carboxamide

A solution of bis(trichloromethyl) carbonate (100 mg, 0.34 mmol) in THF(2.0 mL) was added to a solution of pyridine (0.140 mL, 1.73 mmol) and(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(300 mg, 0.87 mmol) in THF (3.0 mL) at 0° C., and the mixture wasstirred for 10 min. To the reaction mixture was added a solution of(R)-(+)-3-hydroxypyrrolidine (0.180 mL, 2.16 mmol) in DMF (5.0 mL) at 0°C., and the mixture was stirred at room temperature for 1 hr. To thereaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 50→100% ethyl acetate/hexane, 0→10%MeOH/ethyl acetate), and crystallized from ethyl acetate/hexane to givethe title compound (25.4 mg, 0.055 mmol, 6.38%) as white crystals.

MS(API): Calculated 459.6, Found 460.3 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 1.68-1.96 (2H, m), 3.12-3.25(1H, m), 3.34-3.42 (3H, m), 3.73 (3H, s), 4.25 (1H, brs), 4.88 (1H, d,J=3.4 Hz), 5.42 (1H, d, J=7.9 Hz), 6.32 (1H, d, J=7.9 Hz), 6.86-6.94(2H, m), 7.24-7.43 (4H, m), 7.51 (1H, dd, J=11.3, 1.5 Hz), 10.40 (1H,s).

Example 72N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxypropanamide

A solution of(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.26 mmol), 3-hydroxypropanoic acid (26.2 mg, 0.29 mmol), DIEA(0.092 mL, 0.53 mmol) and HATU (121 mg, 0.32 mmol) in DMF (2.0 mL) wasstirred at room temperature for 2 hr. To the reaction mixture were addedwater and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0→50% ethyl acetate/hexane), and crystallized from ethylacetate/hexane to give the title compound (24.3 mg, 0.054 mmol, 20.41%)as a white solid.

MS(API): Calculated 450.6, Found 451.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 2.33-2.43 (2H, m), 3.27 (3H,s), 3.56-3.67 (2H, m), 4.38 (2H, s), 4.62 (1H, t, J=4.9 Hz), 5.58 (1H,d, J=7.6 Hz), 7.16-7.26 (2H, m), 7.28-7.35 (2H, m), 7.39-7.48 (2H, m),8.66 (1H, d, J=7.6 Hz), 10.69 (1H, s).

[α]_(D) ²⁵−109.1 (c 0.1755, MeOH)

Example 733-cyano-N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)propanamide

A solution of(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.26 mmol), 3-cyanopropanoic acid (28.8 mg, 0.29 mmol), DIEA(0.092 mL, 0.53 mmol) and HATU (121 mg, 0.32 mmol) in DMF (2.0 mL) wasstirred at room temperature for 2 hr. To the reaction mixture were addedwater and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0→50% ethyl acetate/hexane) to give the title compound (49.1mg, 0.107 mmol, 40.4%) as a white solid.

MS(API): Calculated 459.6, Found 458.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 2.57-2.69 (4H, m), 3.27 (3H,s), 4.39 (2H, s), 5.50-5.65 (1H, m), 7.17-7.25 (2H, m), 7.28-7.36 (2H,m), 7.40-7.48 (2H, m), 8.89 (1H, d, J=7.6 Hz), 10.74 (1H, s).

Example 74(2R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)amino)acetamide

A solution of(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(200 mg, 0.53 mmol), 2-(5-methyl-1,3,4-oxadiazol-2-yl)acetic acid (83mg, 0.58 mmol), HATU (221 mg, 0.58 mmol) and DIEA (0.102 mL, 0.58 mmol)in DMF (5 mL) was stirred at room temperature for 3 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→90% ethyl acetate/hexane) to givethe title compound (107 mg, 0.213 mmol, 40.3% s) as a white solid.

MS(API): Calculated 502.6, Found 501.2 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 2.46 (3H, s), 3.19-3.30 (3H,m), 3.98 (2H, s), 4.39 (2H, s), 5.57 (1H, d, J=7.2 Hz), 7.21 (2H, d,J=9.8 Hz), 7.28-7.40 (2H, m), 7.41-7.54 (2H, m), 9.20 (1H, d, J=7.2 Hz),10.76 (1H, s).

[α]_(D) ²⁵−106.3 (c 0.2430, MeOH)

Example 75(2R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide

(Step 1)

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), 2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetic acid (71.2mg, 0.31 mmol), DIEA (0.097 mL, 0.55 mmol) and HATU (127 mg, 0.33 mmol)in DMF (2.0 mL) was stirred at room temperature for 2 hr. To thereaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane) to give(R)-2-(2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetamide)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(110.2 mg, 0.191 mmol, 69.0%) as a colorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.22-0.29 (9H, m), 3.38 (3H, s), 3.70 (2H, s),4.42 (2H, s), 5.24 (2H, s), 5.65 (1H, d, J=6.8 Hz), 5.91 (1H, s), 7.03(1H, dd, J=8.1, 1.7 Hz), 7.17-7.25 (1H, m), 7.27-7.46 (11H, m), 7.92(1H, s).

(Step 2)

A solution of(R)-2-(2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetamide)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(110 mg, 0.19 mmol) and 10% palladium-barium sulfate (50 mg, 0.046 mmol)in MeOH (3.0 mL) was stirred at room temperature for 5 hr under hydrogenatmosphere (1 atm). The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (solvent gradient;0→50% ethyl acetate/hexane), and crystallized from ethyl acetate/hexaneto give the title compound (47.3 mg, 0.097 mmol, 51.0%) as a whitesolid.

MS(API): Calculated 485.6, actual measured value 486.2 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 3.27 (3H, s), 3.72 (2H, s),4.39 (2H, s), 5.61 (1H, d, J=7.2 Hz), 5.84 (1H, s), 7.24-7.39 (4H, m),7.42-7.53 (3H, m), 9.03 (1H, d, J=7.2 Hz), 10.60 (1H, s), 11.12 (1H,brs).

[α]_(D) ²⁵−108.8 (c 0.2530, MeOH)

Example 76(2R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide

(Step 1)

A solution of(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(115 mg, 0.30 mmol), 2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetic acid (78mg, 0.33 mmol), DIEA (43.2 mg, 0.33 mmol) and HATU (127 mg, 0.33 mmol)in DMF (2 mL) was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→60% ethyl acetate/hexane) to give(R)-2-(2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetamide)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamideas an oil. The total amount of this compound was used for the reactionin Step 2, without purification.

(Step 2)

A solution of(R)-2-(2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetamide)-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamideobtained in Step 1 and 10% palladium-barium sulfate (32.3 mg, 0.030mmol) in EtOH (4 mL) was stirred at room temperature for 5 hr underhydrogen atmosphere (1 atm). The catalyst was removed by filtration, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 20→100% ethyl acetate/hexane) to give the title compound (45.0mg, 0.089 mmol, 29.4%) as a white solid.

MS(API): Calculated 503.6, actual measured value 502.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 3.27 (3H, s), 3.71 (2H, s),4.39 (2H, s), 5.56 (1H, d, J=7.2 Hz), 5.84 (1H, s), 7.21 (2H, d, J=9.8Hz), 7.28-7.38 (2H, m), 7.39-7.50 (2H, m), 9.05 (1H, d, J=7.6 Hz), 10.75(1H, s) (The free 1H was not observed.).

Example 77N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide(2.9 g) was subjected to optical resolution using chiral columnchromatography. The preparative fraction having a shorter retention timewas concentrated to give the title compound (1.58 g, >99.9% ee) as awhite solid.

purification condition using chiral column chromatography

column: CHIRALPAK IA(NL001)50 mmID×500 mmL

solvent: hexane/EtOH/acetic acid=500/500/1

flow rate: 60 mL/min

temperature: room temperature

detection method: UJV 220 nm

[α]_(D) ²⁵−165.0 (c 0.2445, MeOH)

MS(API): Calculated 503.6, Found 502.1 (M−H).

Example 78(2R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((4-oxopyridin-1(4H)-yl)acetyl)amino)acetamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(140 mg, 0.39 mmol), 2-(4-oxopyridin-1(4H)-yl)acetic acid (65.4 mg, 0.43mmol), HATU (207 mg, 0.54 mmol) and DIEA (0.136 mL, 0.78 mmol) in DMF (2mL) was stirred at room temperature for 1 hr. To the reaction mixturewere added water and ethyl acetate, and the organic layer was separated.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent gradient; 3→25% MeOH/ethyl acetate) to give the title compound(70.9 mg, 0.143 mmol, 36.8%) as white crystals.

MS(API): Calculated 495.6, Found 496.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 3.27 (3H, s), 4.39 (2H, s),4.69 (2H, s), 5.64 (1H, d, J=7.6 Hz), 6.03 (2H, d, J=7.6 Hz), 7.22-7.39(4H, m), 7.42-7.59 (5H, m), 9.15 (1H, d, J=7.6 Hz), 10.63 (1H, s).

Example 79N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)propanamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(80 mg, 0.22 mmol), propionic acid (18.08 mg, 0.24 mmol), DIEA (0.078mL, 0.44 mmol) and HATU (101 mg, 0.27 mmol) in DMF (2.0 mL) was stirredat room temperature for 1 hr. To the reaction mixture were added waterand ethyl acetate, and the organic layer was separated. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 0→50%ethyl acetate/hexane) to give the title compound (24.3 mg, 0.058 mmol,26.3%) as white crystals.

MS(API): Calculated 416.6, Found 417.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 0.99 (3H, t, J=7.6 Hz), 2.23(2H, q, J=7.6 Hz), 3.27 (3H, s), 4.38 (2H, s), 5.61 (1H, d, J=7.6 Hz),7.24-7.38 (4H, m), 7.40-7.55 (3H, m), 8.58 (1H, d, J=7.6 Hz), 10.56 (1H,s).

Example 80N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3-(methylsulfonyl)propanamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), 3-(methylsulfonyl)propanoic acid (46.4 mg, 0.31mmol), DIEA (0.097 mL, 0.55 mmol) and HATU (127 mg, 0.33 mmol) in DMF(2.0 mL) was stirred at room temperature for 2 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (24.3mg, 0.049 mmol, 17.71%) as white crystals.

MS(API): Calculated 494.7, Found 495.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 2.67-2.79 (2H, m), 2.97 (3H,s), 3.27 (3H, s), 3.29-3.38 (2H, m), 4.38 (2H, s), 5.61 (1H, d, J=7.2Hz), 7.23-7.39 (4H, m), 7.41-7.55 (3H, m), 8.93 (1H, d, J=7.2 Hz), 10.56(1H, s).

Example 81(2R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((methylsulfonyl)acetyl)amino)acetamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), 2-(methylsulfonyl)acetic acid (42.2 mg, 0.31 mmol),HATU (148 mg, 0.39 mmol) and DIEA (0.097 mL, 0.55 mmol) in DMF (2 mL)was stirred at room temperature for 1 hr. To the reaction mixture wereadded water and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 1→73% MeOH/ethyl acetate), and crystallized from EtOH/water togive the title compound (76 mg, 0.158 mmol, 57.0%) as white crystals.

MS(API): Calculated 480.6, Found 481.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 3.10 (3H, s), 3.27 (3H, s),4.20-4.35 (2H, m), 4.39 (2H, s), 5.58-5.69 (1H, m), 7.24-7.54 (7H, m),9.20 (1H, d, J=7.6 Hz), 10.63 (1H, s).

[α]_(D) ²⁵−93.8 (c 0.2490, MeOH)

Example 82N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxy-1,2-oxazole-5-carboxamide

A solution of(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(800 mg, 2.11 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (327 mg,2.54 mmol), DIEA (0.723 mL, 4.23 mmol) and HATU (1086 mg, 2.54 mmol) inDMF (15 mL) was stirred at room temperature for 5 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (649.0mg, 1.326 mmol, 62.7%) as white crystals.

MS(API): Calculated 489.5, Found 490.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 3.28 (3H, s), 4.40 (2H, s),5.71 (1H, d, J=7.2 Hz), 6.79-6.83 (1H, m), 7.21 (1H, s), 7.24 (1H, s),7.34 (2H, d, J=8.3 Hz), 7.47 (2H, d, J=8.3 Hz), 9.41 (1H, d, J=7.2 Hz),10.75 (1H, s), 11.69 (1H, s).

[α]_(D) ²⁵−126.8 (c 0.2020, MeOH)

Example 83N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-1,2-oxazole-5-carboxamide

To a solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(1.25 g, 3.61 mmol), DIEA (1.234 mL, 7.22 mmol) and3-hydroxy-1,2-oxazole-5-carboxylic acid (0.559 g, 4.33 mmol) in DMF (25mL) was added HATU (1.854 g, 4.33 mmol), and the mixture was stirred atroom temperature for 5 hr. To the reaction mixture were added water andethyl acetate, and the organic layer was separated. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 10→50% ethylacetate/hexane), and crystallized from ethyl acetate/hexane to give thetitle compound (1.01 g, 2.208 mmol, 61.2%) as white crystals.

MS(API): Calculated 457.5, Found 458.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 3.74 (3H, s), 5.67 (1H, d,J=7.2 Hz), 6.81 (1H, s), 6.91-7.00 (2H, m), 7.24-7.38 (2H, m), 7.39-7.55(3H, m), 9.28 (1H, d, J=7.2 Hz), 10.55 (1H, s), 11.68 (1H, s).

[α]_(D) ²⁵−150.4 (c 0.1890, MeOH)

Example 842,2-difluoro-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)cyclopropanecarboxamide(Mixture of Two Diastereomers)

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(90 mg, 0.25 mmol), 2,2-difluorocyclopropanecarboxylic acid (33.5 mg,0.27 mmol), HATU (104 mg, 0.27 mmol) and DIEA (0.048 mL, 0.27 mmol) inDMF (3 mL) was stirred overnight at room temperature. To the reactionmixture was added water, and the precipitate was collected by filtrationto give the title compound (111 mg, 0.239 mmol, 96%) as white crystals.

MS(API): Calculated 464.6, Found 465.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.19-0.30 (9H, m), 1.79-1.98 (2H, m),2.77-2.95 (1H, m), 3.25-3.29 (3H, m), 4.39 (2H, s), 5.53-5.75 (1H, m),7.24-7.38 (4H, m), 7.41-7.55 (3H, m), 9.14-9.28 (1H, m), 10.58-10.68(1H, m).

Example 85(2R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(glycoloylamino)-2-(4-(methoxymethyl)phenyl)acetamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(80 mg, 0.22 mmol), 2-hydroxyacetic acid (18.56 mg, 0.24 mmol), DIEA(0.078 mL, 0.44 mmol) and HATU (101 mg, 0.27 mmol) in DMF (2.0 mL) wasstirred at room temperature for 2 hr. To the reaction mixture were addedwater and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0→50% ethyl acetate/hexane) to give the title compound (34.5mg, 0.082 mmol, 37.1%) as a white solid.

MS(API): Calculated 418.5, Found 419.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 3.27 (3H, s), 3.90 (2H, d,J=6.0 Hz), 4.38 (2H, s), 5.59-5.70 (2H, m), 7.25-7.53 (7H, m), 8.15 (1H,d, J=7.9 Hz), 10.66 (1H, s).

Example 86N²-acetyl-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)glycinamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), 2-acetamidoacetic acid (35.7 mg, 0.31 mmol), DIEA(0.097 mL, 0.55 mmol) and HATU (127 mg, 0.33 mmol) in DMF (2.0 mL) wasstirred at room temperature for 2 hr. To the reaction mixture were addedwater and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 50→100% ethyl acetate/hexane), and crystallized from ethylacetate/hexane to give the title compound (73.4 mg, 0.160 mmol, 57.6%)as white crystals.

MS(API): Calculated 459.6, Found 460.3 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, d, J=0.8 Hz), 1.85 (3H, s), 3.27(3H, s), 3.77-3.84 (2H, m), 4.38 (2H, s), 5.57-5.65 (1H, m), 7.26-7.38(4H, m), 7.41-7.53 (3H, m), 8.11 (1H, t, J=5.7 Hz), 8.68 (1H, d, J=7.6Hz), 10.56 (1H, s).

Example 871-acetyl-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)piperidine-4-carboxamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), 1-acetylpiperidine-4-carboxylic acid (52.2 mg, 0.31mmol), DIEA (0.097 mL, 0.55 mmol) and HATU (127 mg, 0.33 mmol) in DMF(2.0 mL) was stirred at room temperature for 2 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 50→100% ethyl acetate/hexane) to givethe title compound (67.1 mg, 0.131 mmol, 47.1%) as a white solid.

MS(API): Calculated 513.7, Found 512.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 1.21-1.57 (3H, m), 1.61-1.79(2H, m), 1.95-2.00 (3H, m), 2.56-2.67 (1H, m), 2.91-3.08 (1H, m), 3.27(3H, s), 3.81 (1H, brs), 4.38 (3H, s), 5.60 (1H, dd, J=7.4, 2.5 Hz),7.24-7.37 (4H, m), 7.40-7.53 (3H, m), 8.60-8.68 (1H, m), 10.56 (1H, s).

Example 88N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)tetrahydro-2H-pyran-4-carboxamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), tetrahydro-2H-pyran-4-carboxylic acid (39.7 mg,0.31 mmol), DIEA (0.097 mL, 0.55 mmol) and HATU (127 mg, 0.33 mmol) inDMF (2.0 mL) was stirred at room temperature for 2 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (68.3mg, 0.145 mmol, 52.1%) as white crystals.

MS(API): Calculated 472.6, Found 473.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 1.48-1.67 (4H, m), 2.55-2.69(1H, m), 3.21-3.32 (5H, m), 3.78-3.91 (2H, m), 4.38 (2H, s), 5.55-5.64(1H, m), 7.23-7.38 (4H, m), 7.41-7.53 (3H, m), 8.61 (1H, d, J=7.9 Hz),10.56 (1H, s).

Example 89(2R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-((tetrahydro-2H-pyran-4-ylacetyl)amino)acetamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), 2-(tetrahydro-2H-pyran-4-yl)acetic acid (44.0 mg,0.31 mmol), DIEA (0.097 mL, 0.55 mmol) and HATU (127 mg, 0.33 mmol) inDMF (2.0 mL) was stirred at room temperature for 2 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (39.8mg, 0.082 mmol, 29.5%) as white crystals.

MS(API): Calculated 486.7, Found 487.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 1.05-1.30 (2H, m), 1.43-1.61(2H, m), 1.80-2.02 (1H, m), 2.11-2.21 (2H, m), 3.19-3.30 (5H, m),3.73-3.85 (2H, m), 4.38 (2H, s), 5.55-5.64 (1H, m), 7.23-7.37 (4H, m),7.40-7.53 (3H, m), 8.64 (1H, d, J=7.6 Hz), 10.55 (1H, s).

Example 90(2R)-2-((ethylcarbamoyl)amino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide

To a solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol) and TEA (0.046 mL, 0.33 mmol) in THF (2.0 mL) wasadded ethyl isocyanate (0.024 mL, 0.31 mmol), and the mixture wasstirred at room temperature for 2 hr. The reaction mixture wasconcentrated under reduced pressure, and the residue was crystallizedfrom ethyl acetate/hexane to give the title compound (95.5 mg, 0.221mmol, 80-) as white crystals.

MS(API): Calculated 431.6, Found 432.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, d, J=0.8 Hz), 0.98 (3H, t, J=7.2Hz), 2.92-3.09 (2H, m), 3.26 (3H, s), 4.37 (2H, s), 5.43-5.52 (1H, m),6.14 (1H, t, J=5.3 Hz), 6.74 (1H, d, J=8.3 Hz), 7.26-7.43 (6H, m), 7.49(1H, dd, J=11.1, 1.3 Hz), 10.58 (1H, s).

Example 913,3-difluoro-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)cyclobutanecarboxamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(113 mg, 0.31 mmol), 3,3-difluorocyclobutanecarboxylic acid (46.9 mg,0.34 mmol), HATU (131 mg, 0.34 mmol) and DIEA (0.060 mL, 0.34 mmol) inDMF (3 mL) was stirred at room temperature for 2 hr. To the reactionmixture was added water, and the precipitate was collected byfiltration, and washed with water to give the title compound (133 mg,0.278 mmol, 89%) as white crystals.

MS(API): Calculated 478.6, Found 479.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 2.58-2.79 (4H, m), 3.13 (1H,td, J=8.4, 4.0 Hz), 3.27 (3H, s), 4.38 (2H, s), 5.54-5.65 (1H, m),7.22-7.37 (4H, m), 7.39-7.54 (3H, m), 8.88 (1H, d, J=7.6 Hz), 10.59 (1H,s).

Example 924,4-difluoro-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)butanamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), 4,4-difluorobutanoic acid (37.9 mg, 0.31 mmol),HATU (116 mg, 0.31 mmol) and DIEA (0.053 mL, 0.31 mmol) in DMF (3 mL)was stirred overnight at room temperature. To the reaction mixture wasadded water, and the precipitate was collected by filtration. Theobtained precipitate was purified by silica gel column chromatography(solvent; ethyl acetate), and crystallized from ethyl acetate/hexane togive the title compound (107 mg, 0.229 mmol, 83%) as white crystals.

MS(API): Calculated 466.6, Found 467.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 1.91-2.17 (2H, m), 2.37-2.43(2H, m), 3.27 (3H, s), 4.38 (2H, s), 5.56-5.64 (1H, m), 6.08 (1H, tt,J=57.0, 4.3 Hz), 7.24-7.38 (4H, m), 7.40-7.55 (3H, m), 8.80 (1H, d,J=7.6 Hz), 10.57 (1H, s).

Example 933,3,3-trifluoro-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)propanamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), 3,3,3-trifluoropropanoic acid (0.027 mL, 0.31mmol), HATU (116 mg, 0.31 mmol) and DIEA (0.053 mL, 0.31 mmol) in DMF (3mL) was stirred at room temperature for 2 hr. To the reaction mixturewere added water and ethyl acetate, and the organic layer was separated.The organic layer was washed with brine, and dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(solvent; 50% ethyl acetate/hexane), and crystallized from acetone/waterto give the title compound (36 mg, 0.077 mmol, 27.6%) as white crystals.

MS(API): Calculated 470.5, Found 471.1 (M+H).

¹H NMR (300 MHz, CDCl₃): δ0.27 (9H, d, J=0.8 Hz), 3.14 (2H, q, J=10.6Hz), 3.40 (3H, s), 4.45 (2H, s), 5.57 (1H, d, J=6.4 Hz), 7.02 (1H, dd,J=7.9, 1.9 Hz), 7.20 (1H, s), 7.27-7.31 (2H, m), 7.31-7.45 (5H, m).

Example 944,4,4-trifluoro-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)butanamide

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol), 4,4,4-trifluorobutanoic acid (43.4 mg, 0.31 mmol),HATU (116 mg, 0.31 mmol) and DIEA (0.053 mL, 0.31 mmol) in DMF (3 mL)was stirred at room temperature for 4 hr. To the reaction mixture wasadded water, and the precipitate was collected by filtration. Theobtained precipitate was washed with water to give the title compound(115 mg, 0.237 mmol, 86%) as white crystals.

MS(API): Calculated 484.6, Found 485.2 (M+H).

¹H NMR (300 MHz, CDCl₃): δ 0.27 (9H, d, J=0.8 Hz), 2.36-2.61 (4H, m),3.40 (3H, s), 4.45 (2H, s), 5.55 (1H, d, J=6.8 Hz), 6.87 (1H, d, J=6.4Hz), 7.02 (1H, dd, J=7.9, 1.9 Hz), 7.20-7.31 (2H, m), 7.33-7.45 (5H, m).

Example 95(3R)-3-fluoro-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)pyrrolidine-1-carboxamide

(Step 1)

To a solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(270 mg, 0.75 mmol) in THF (6 mL) were added p-nitrophenyl chloroformate(174 mg, 0.86 mmol) and pyridine (0.069 mL, 0.86 mmol), and the mixturewas stirred at room temperature for 1 hr. The precipitate was collectedby filtration. The obtained precipitate was washed successively withwater and hexane to give 4-nitrophenyl((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(320 mg, 0.609 mmol, 81%) as a white solid.

(Step 2)

To a solution of (R)-3-fluoropyrrolidine hydrochloride (203 mg, 1.62mmol) and DIEA (0.847 mL, 4.85 mmol) in DMF (5 mL) was added dropwise asolution of 4-nitrophenyl((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(170 mg, 0.32 mmol) in DMF (2 mL) at 0° C., and the mixture was stirredat 0° C. for 30 min. To the reaction mixture were added water and ethylacetate, and the organic layer was separated. The organic layer waswashed with water and brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent gradient; 30→100%ethyl acetate/hexane, 0→10% MeOH/ethyl acetate) to give the titlecompound (28 mg, 0.059 mmol, 18.20%) as a white solid.

MS(API): Calculated 475.6, Found 476.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 1.90-2.18 (2H, m), 3.27 (3H,s), 3.30-3.65 (4H, m), 4.38 (2H, s), 5.18-5.44 (1H, m), 5.78 (1H, dd,J=339.9, 7.5 Hz), 5.50 (1H, s), 7.24-7.39 (4H, m), 7.42-7.57 (3H, m),10.48 (1H, s).

Example 96(3S)-3-fluoro-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)pyrrolidine-1-carboxamide

To a solution of (S)-3-fluoropyrrolidine hydrochloride (196 mg, 1.56mmol) and DIEA (0.822 mL, 4.71 mmol) in DMF (5 mL) was added a solutionof 4-nitrophenyl((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(165 mg, 0.31 mmol) in DMF (2 mL) at 0° C., and the mixture was stirredat 0° C. for 1 hr. To the reaction mixture were added water and ethylacetate, and the organic layer was separated. The organic layer waswashed with water and brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure to give the title compound(56 mg, 0.118 mmol, 37.5%) as a white solid.

MS(API): Calculated 475.6, Found 476.3 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, d, J=0.8 Hz), 1.91-2.21 (2H, m),3.27 (3H, s), 3.28-3.72 (4H, m), 4.38 (2H, s), 5.18-5.43 (1H, m), 5.95(1H, dd, J=342.9, 7.9 Hz), 5.49 (1H, s), 7.22-7.40 (4H, m), 7.42-7.59(3H, m), 10.47 (1H, s).

Example 97(2R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-((morpholin-4-ylacetyl)amino)acetamidehydrochloride

A solution of(R)-2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(156 mg, 0.43 mmol), 2-morpholinoacetic acid (62.7 mg, 0.43 mmol), DIEA(0.085 mL, 0.48 mmol) and HATU (181 mg, 0.48 mmol) in DMF (2 mL) wasstirred at room temperature for 1 hr. To the reaction mixture were addedwater and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by preparative HPLC (C18, mobile phase:water/acetonitrile (containing 0.1% TFA)), treated with 1 mol equivalentof hydrogen chloride/ethyl acetate, and crystallized from to give thetitle compound (80 mg, 0.153 mmol, 35.3%) as a white solid.

MS(API): Calculated 524.1, Found 488.2 (M−HCl+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.25 (9H, s), 1.04 (1H, d, J=6.0 Hz),3.11-3.30 (6H, m), 3.65-4.19 (6H, m), 4.39 (2H, s), 5.68 (1H, d, J=7.2Hz), 7.24-7.41 (4H, m), 7.42-7.59 (3H, m), 9.48 (1H, brs), 10.41-11.02(2H, m).

Example 98N-((1R)-2-((2,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxy-1,2-oxazole-5-carboxamide

A solution of(R)-2-amino-N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(161 mg, 0.43 mmol), 3-hydroxy-1,2-oxazole-5-carboxylic acid (60.4 mg,0.47 mmol), HATU (178 mg, 0.47 mmol) and DIEA (0.082 mL, 0.47 mmol) inDMF (5 mL) was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→100% ethyl acetate/hexane) to givethe title compound (40.0 mg, 0.082 mmol, 19.21%) as a white solid.

MS(API): Calculated 489.5, Found 490.1 (M+H).

Example 99N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-1,2-oxazole-5-carboxamide

(Step 1)

A solution of2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-methoxyphenyl)acetamide(0.853 g, 2.34 mmol), HATU (0.979 g, 2.57 mmol), DIEA (0.450 mL, 2.57mmol) and 3-hydroxy-1,2-oxazole-5-carboxylic acid (0.332 g, 2.57 mmol)in DMF (2 mL) was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate/hexane, MeOH/ethyl acetate) togiveN-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-1,2-oxazole-5-carboxamide(835 mg, 1.756 mmol, 75.0%) as a white solid.

(Step 2)

N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-1,2-oxazole-5-carboxamide(2.72 g) was subjected to optical resolution using chiral columnchromatography. The preparative fraction having a longer retention timewas concentrated to give the title compound (680.0 mg, >99.9% ee) as awhite solid.

MS(API): Calculated 475.5, Found 476.2 (M+H).

purification condition using chiral column chromatography

column: CHIRALPAK AD-H(PF001)30 mmID×250 mmL

solvent: CO₂/EtOH=660/340

back pressure: 100 bar

temperature: 35° C.

detection method: UV 220 nm

[α]_(D) ²⁵−134.1 (c 0.1440, MeOH)

Example 100(2R)—N-(4-tert-butyl-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)-2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

(Step 1)

2-(tert-Butyl)aniline (10 g, 67.01 mmol) was slowly added dropwise tosulfuric acid (63.8 mL, 670.09 mmol) while the mixture was kept at 10°C. or lower. Then, potassium nitrate (6.77 g, 67.01 mmol) was slowlyadded thereto while the mixture was kept at 10° C. or lower. Thereaction mixture was stirred at 5° C. for 30 min, and then at roomtemperature for 1 hr. The reaction mixture was poured into ice (ca, 500g), and the mixture was extracted with diethyl ether. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent; 20% ethyl acetate/hexane),and crystallized from hexane to give 2-(tert-butyl)-5-nitroaniline(12.26 g, 63.1 mmol, 94-) as a pale yellow solid.

¹H NMR (300 MHz, CDCl₃): δ1.44 (9H, s), 3.81-4.32 (2H, m), 7.34 (1H, d,J=8.7 Hz), 7.46 (1H, d, J=2.3 Hz), 7.49-7.59 (1H, m).

(Step 2)

A solution of 2-(tert-butyl)-5-nitroaniline (2054 mg, 10.58 mmol) andnitrosonium tetrafluoroborate (0.920 mL, 17.21 mmol) ino-dichlorobenzene (20 mL) was stirred at 0° C. for 1 hr. The reactionmixture was stirred at 110° C. for 1 hr, cooled, and poured into water.The mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0-10% ethylacetate/hexane) to give 1-(tert-butyl)-2-fluoro-4-nitrobenzene (1600 mg,8.11 mmol, 60.4%) as a brown oil.

¹H NMR (300 MHz, CDCl₃): δ1.42 (9H, d, J=1.1 Hz), 7.48 (1H, t, J=8.3Hz), 7.87 (1H, dd, J=11.9, 2.5 Hz), 7.96 (1H, dd, J=8.7, 2.3 Hz).

(Step 3)

A solution of 1-(tert-butyl)-2-fluoro-4-nitrobenzene (1.6 g, 8.11 mmol)and 10% palladium-carbon (0.432 g, 0.20 mmol, 50% wet) in EtOH (20 mL)was stirred at room temperature for 5 hr under hydrogen atmosphere (1atm). The catalyst was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 0→20% ethylacetate/hexane) to give 4-(tert-butyl)-3-fluoroaniline (1.310 g, 7.83mmol, 97%) as a brown oil.

¹H NMR (300 MHz, CDCl₃): δ1.32 (9H, d, J=1.1 Hz), 3.61 (2H, brs),6.26-6.46 (2H, m), 6.95-7.12 (1H, m).

(Step 4)

A solution of 2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid(1.811 g, 6.58 mmol), T3P (4.22 mL, 7.18 mmol), DMAP (0.731 g, 5.98mmol), DIEA (2.089 mL, 11.96 mmol) and 4-(tert-butyl)-3-fluoroaniline (1g, 5.98 mmol) in ethyl acetate (20 mL) was stirred overnight at 60° C.To the reaction mixture were added water and ethyl acetate, and theorganic layer was separated. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→50% ethyl acetate/hexane) to giveN-(4-(tert-butyl)-3-fluorophenyl)-2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetamide(1.450 g, 3.42 mmol, 57.1%) as a brown oil.

¹H NMR (300 MHz, CDCl₃): δ1.36 (9H, s), 2.88 (2H, dd, J=14.7, 7.2 Hz),3.33 (2H, dd, J=14.7, 5.3 Hz), 3.40 (3H, s), 4.34-4.63 (3H, m),5.13-5.38 (4H, m), 5.85 (2H, dddd, J=17.4, 9.9, 7.1, 5.3 Hz), 7.06-7.24(2H, m), 7.27-7.53 (5H, m), 9.41 (1H, s).

(Step 5)

A solution ofN-(4-(tert-butyl)-3-fluorophenyl)-2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetamide(1.45 g, 3.42 mmol), 1,3-dimethylbarbituric acid (1.173 g, 7.51 mmol)and Pd(PPh₃)₄(0.158 g, 0.14 mmol) in THF (20 mL) was stirred overnightat room temperature. To the reaction mixture were added water and ethylacetate, and the organic layer was separated. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (NH, solvent gradient; 2-100% ethylacetate/hexane) to give2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(0.891 g, 2.59 mmol, 76%) as a brown oil.

¹H NMR (300 MHz, CDCl₃): δ1.34 (9H, s), 3.37 (3H, s), 4.44 (2H, s), 4.64(1H, s), 7.10-7.25 (2H, m), 7.28-7.75 (7H, m), 9.38 (1H, brs).

(Step 6)

A solution of2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(890 mg, 2.58 mmol), allyl chloroformate (0.288 ML, 2.71 mmol) and DIEA(0.677 mL, 3.88 mmol) in THF (10 mL) was stirred at 0° C. for 1 hr. Tothe reaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→50% ethyl acetate/hexane) to giveallyl(2-((4-(tert-butyl)-3-fluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(774 mg, 1.806 mmol, 69.9) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ1.33 (9H, d, J=0.8 Hz), 3.38 (3H, s), 4.44(2H, s), 4.57 (2H, ddd, J=4.2, 2.9, 1.5 Hz), 5.08-5.41 (3H, m),5.60-6.37 (2H, m), 6.71-7.22 (2H, m), 7.28-7.76 (6H, m).

(Step 7)

Allyl(2-((4-(tert-butyl)-3-fluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(350 mg) was subjected to optical resolution using chiral columnchromatography. The preparative fraction having a longer retention timewas concentrated to give allyl(R)-(2-((4-(tert-butyl)-3-fluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(345.3 mg, >99.9% ee) as a white solid.

purification condition using chiral column chromatography

column: CHIRALPAK AD(NF001)50 mmID×500 mmL

solvent: hexane/EtOH=800/200

flow rate: 80 mL/min

temperature: 30° C.

detection method: UJV 220 nm

(Step 8)

A solution of allyl(R)-(2-((4-(tert-butyl)-3-fluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(339.2 mg, 0.79 mmol), Pd(PPh₃)₄(27.4 mg, 0.02 mmol) and1,3-dimethylbarbituric acid (247 mg, 1.58 mmol) in acetonitrile (10 mL)was stirred overnight at room temperature. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (solvent gradient; 10→100%ethyl acetate/hexane) to give(R)-2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(190 mg, 0.552 mmol, 69.7%) as a brown oil.

(Step 9)

A solution of(R)-2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(90 mg, 0.26 mmol), 2-(6-oxopyrimidin-1(6H)-yl)acetic acid (44.3 mg,0.29 mmol), HATU (109 mg, 0.29 mmol) and DIEA (0.052 mL, 0.29 mmol) inDMF (5 mL) was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→100% ethyl acetate/hexane), andcrystallized from ethyl acetate/hexane to give the title compound (90mg, 0.187 mmol, 71.7%) as white crystals.

MS(API): Calculated 480.5, Found 481.2 (M−H).

Example 101(3S)—N-((1R)-2-((4-tert-butyl-3-fluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

A solution of(R)-2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(50 mg, 0.15 mmol), (S)-5-oxopyrrolidine-3-carboxylic acid (18.74 mg,0.15 mmol), HATU (60.7 mg, 0.16 mmol) and DIEA (0.029 mL, 0.16 mmol) inDMF (5 mL) was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 20→100% ethyl acetate/hexane, 1→15%MeOH/ethyl acetate), and crystallized from ethyl acetate/hexane to givethe title compound (12.00 mg, 0.026 mmol, 18.15%) as white crystals.

MS(API): Calculated 455.5, Found 454.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ1.29 (9H, s), 2.16-2.40 (2H, m), 3.27 (5H,s), 4.38 (2H, s), 5.60 (1H, d, J=7.6 Hz), 7.14-7.37 (4H, m), 7.38-7.61(4H, m), 8.83 (1H, d, J=7.9 Hz), 10.50 (1H, s) (The free 1H was notobserved.).

[α]_(D) ²⁵−116.8 (c 0.2065, MeOH)

Example 102(3R)—N-((1R)-2-((4-tert-butyl-3-fluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

A solution of(R)-2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(50 mg, 0.15 mmol), (R)-5-oxopyrrolidine-3-carboxylic acid (20.62 mg,0.16 mmol), HATU (60.7 mg, 0.16 mmol) and DIEA (0.029 mL, 0.16 mmol) inDMF (5 mL) was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→100% ethyl acetate/hexane, 1→15%MeOH/ethyl acetate) to give the title compound (10.00 mg, 0.022 mmol,15.12%) as white crystals.

MS(API): Calculated 455.5, Found 454.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ1.29 (9H, s), 2.26 (2H, dd, J=7.9, 2.6 Hz),3.27 (5H, s), 4.38 (2H, s), 5.58 (1H, d, J=7.6 Hz), 7.11-7.37 (4H, m),7.37-7.63 (4H, m), 8.81 (1H, d, J=7.6 Hz), 10.48 (1H, s) (The free 1Hwas not observed.).

Example 1034-(((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)amino)-2,2-dimethyl-4-oxobutanoicacid

A solution of(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.26 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (35.5 mg,0.28 mmol) in THF (2.0 mL) was stirred at room temperature for 3 hr. Thereaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(solvent gradient; 0→15% ethyl acetate/hexane), and then preparativeHPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) togive the title compound (42.2 mg, 0.083 mmol, 31.5%) as a white solid.

MS(API): Calculated 506.6, Found 507.2 (M+H).

¹H NMR (300 MHz, DMSO-d_(F)): δ0.30 (9H, s), 1.12 (3H, s), 1.12 (3H, s),3.27 (3H, s), 3.30 (2H, s), 4.38 (2H, s), 5.52 (1H, d, J=7.6 Hz), 7.21(2H, d, J=9.8 Hz), 7.28-7.35 (2H, m), 7.39-7.45 (2H, m), 8.61 (1H, d,J=7.6 Hz), 10.68 (1H, s), 11.92 (1H, brs).

Example 104(3S)—N-(2-((4-tert-butyl-3-chlorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide(Mixture of Two Diastereomers)

(Step 1)

A solution of 2-(tert-butyl)-5-nitroaniline (4 g, 20.59 mmol), pentylnitrite (3.62 g, 30.89 mmol) and copper(I) chloride (2.039 g, 20.59mmol) in acetonitrile (100 mL) was stirred at 50° C. for 2 hr. To thereaction mixture was added 1N hydrochloric acid at room temperature, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 0→5% ethylacetate/hexane) to give 1-(tert-butyl)-2-chloro-4-nitrobenzene (1.760 g,8.24 mmol, 40.0%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ1.52 (9H, s), 7.60 (1H, d, J=9.1 Hz), 8.04(1H, dd, J=8.9, 2.5 Hz), 8.22 (1H, d, J=2.6 Hz).

(Step 2)

A solution of 1-(tert-butyl)-2-chloro-4-nitrobenzene (1.76 g, 8.24mmol), ferric chloride hexahydrate (0.045 g, 0.16 mmol) and activatedcarbon (300 mg) in a mixed solvent of THE (10 mL) and MeOH (10 mL) washeated with reflux for 15 min. Then, a solution of hydrazine monohydrate(2.474 g, 49.42 mmol) in MeOH (5 mL) was added thereto, and the mixturewas heated with reflux for 40 min. The reaction mixture was cooled, andthe insoluble substance was removed by filtration. To the filtrate wereadded water and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over sodium sulfate, andthe solvent was evaporated under reduced pressure to give4-(tert-butyl)-3-chloroaniline (1.420 g, 7.73 mmol, 94%) as a colorlessoil.

¹H NMR (300 MHz, CDCl₃): δ1.43 (9H, s), 3.58 (2H, brs), 6.51 (1H, dd,J=8.5, 2.5 Hz), 6.70 (1H, d, J=2.6 Hz), 7.18 (1H, d, J=8.3 Hz).

(Step 3)

A solution of 4-(tert-butyl)-3-chloroaniline (1.42 g, 7.73 mmol),2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid (2.342 g, 8.50mmol), T3P (5.00 mL, 8.50 mmol), DMAP (1.039 g, 8.50 mmol) and DIEA(1.527 mL, 8.50 mmol) in ethyl acetate (20 mL) was stirred overnight at70° C. To the reaction mixture were added water and ethyl acetate, andthe organic layer was separated. The organic layer was washed withbrine, and dried over magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 10→100% ethyl acetate/hexane)to giveN-(4-(tert-butyl)-3-chlorophenyl)-2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetamide(2.210 g, 5.01 mmol, 64.8%) as a brownish-red oil.

¹H NMR (300 MHz, CDCl₃): δ1.35-1.51 (9H, m), 2.88 (2H, dd, J=14.7, 7.2Hz), 3.22-3.42 (5H, m), 4.46 (2H, s), 4.54 (1H, s), 5.12-5.37 (4H, m),5.73-6.00 (2H, m), 7.27-7.46 (6H, m), 7.60 (1H, d, J=2.3 Hz), 9.37 (1H,s).

(Step 4)

A solution ofN-(4-(tert-butyl)-3-chlorophenyl)-2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetamide(2.21 g, 5.01 mmol), 1,3-dimethylbarbituric acid (1.721 g, 11.02 mmol)and Pd(PPh₃)₄(0.174 g, 0.15 mmol) in THF (20 mL) was stirred overnightat room temperature. The reaction mixture was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (NH, solvent gradient; 10→100% ethyl acetate/hexane) togive2-amino-N-(4-(tert-butyl)-3-chlorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(1.300 g, 3.60 mmol, 71.9%) as a pale yellow oil.

(Step 5)

A solution of2-amino-N-(4-(tert-butyl)-3-chlorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(111 mg, 0.31 mmol), (S)-5-oxopyrrolidine-3-carboxylic acid (43.7 mg,0.34 mmol), HATU (129 mg, 0.34 mmol) and DIEA (0.061 mL, 0.34 mmol) inDMF (5 mL) was stirred at room temperature for 1 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→100% ethyl acetate/hexane, 0→15%MeOH/ethyl acetate) to give the title compound (90 mg, 0.191 mmol,62.0%) as a white solid.

MS(API): Calculated 472.0, Found 470.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ1.39 (9H, brs), 2.30 (2H, brs), 3.27 (5H,brs), 4.38 (2H, brs), 5.57 (1H, brs), 7.17-7.64 (8H, m), 7.74 (1H, brs),8.81 (1H, brs), 10.47 (1H, brs).

Example 105(2R)—N-(4-tert-butyl-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)-2-(((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)amino)acetamide

A solution of(R)-2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(45 mg, 0.13 mmol), lithium 2-(5-methyl-1,3,4-oxadiazol-2-yl)acetate(29.0 mg, 0.20 mmol), HATU (54.6 mg, 0.14 mmol) and DIEA (0.00 mmol) inDMF (5 mL) was stirred at room temperature for 3 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→100% ethyl acetate/hexane) to givethe title compound (40.0 mg, 0.085 mmol, 65.3%) as a yellow oil.

MS(API): Calculated 468.5, Found 469.2 (M+H).

¹H NMR (300 MHz, CDCl₃): δ1.30 (9H, s), 2.40 (3H, d, J=1.1 Hz), 3.35(3H, s), 3.91 (2H, d, J=4.5 Hz), 4.38 (2H, s), 5.78 (1H, d, J=7.2 Hz),6.95-7.17 (2H, m), 7.23 (2H, d, J=7.9 Hz), 7.28-7.45 (3H, m), 8.24 (1H,d, J=7.2 Hz), 8.93 (1H, s).

Example 106(2R)—N-(4-tert-butyl-3-fluorophenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide

(Step 1)

A solution of(R)-2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide (88 mg, 0.26 mmol), 2-(3-(benzyloxy)-1,2-oxazol-5-yl)aceticacid (65.5 mg, 0.28 mmol), HATU (107 mg, 0.28 mmol) and DIEA (0.049 mL,0.28 mmol) in DMF (5 mL) was stirred at room temperature for 3 hr. Tothe reaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 10→50% ethyl acetate/hexane) to give(R)-2-(2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetamide)-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(146 mg, 0.261 mmol, 102%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ1.32 (9H, d, J=0.8 Hz), 2.84-3.03 (3H, m),3.38 (3H, s), 3.56-3.81 (2H, m), 4.33-4.55 (2H, m), 5.16-5.34 (2H, m),5.63 (1H, d, J=6.8 Hz), 5.84-6.04 (1H, m), 6.83-7.21 (2H, m), 7.30-7.57(8H, m), 7.72-8.11 (1H, m).

(Step 2)

A solution of (R)-2-(2-(3-(benzyloxy)-1,2-oxazol-5-yl)acetamide)-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(146 mg, 0.26 mmol) and 5% palladium-barium sulfate (100 mg, 0.05 mmol)in EtOH (5 mL) was stirred at room temperature for 5 hr. The catalystwas removed by filtration, and the filtrate was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 50→100% ethyl acetate/hexane, 0→20%MeOH/ethyl acetate) to give the title compound (50.0 mg, 0.106 mmol,40.8%) as a white solid.

MS(API): Calculated 469.5, Found 470.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ1.29 (9H, s), 3.27 (3H, s), 3.72 (2H, s),4.39 (2H, s), 5.60 (1H, d, J=7.6 Hz), 5.84 (1H, s), 7.16-7.38 (4H, m),7.39-7.57 (3H, m), 9.03 (1H, d, J=7.9 Hz), 10.52 (1H, s), 11.09 (1H, s).

Example 1075-(((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)amino)-5-oxopentanoicacid

A solution of(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(90 mg, 0.24 mmol), dihydro-2H-pyran-2,6(3H)-dione (28.5 mg, 0.25 mmol)and TEA (0.036 mL, 0.26 mmol) in THF (2.0 mL) was stirred at roomtemperature for 3 hr. The reaction mixture was concentrated underreduced pressure, and the obtained residue was purified by silica gelcolumn chromatography (solvent gradient; 0→50% ethyl acetate/hexane).The obtained residue was purified by preparative HPLC (C18, mobilephase: water/acetonitrile (containing 0.1% TFA)) to give the titlecompound (45.1 mg, 0.092 mmol, 38.5%) as a white solid.

MS(API): Calculated 492.6, Found 493.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 1.71 (2H, quin, J=7.3 Hz),2.16-2.31 (4H, m), 3.27 (3H, s), 4.38 (2H, s), 5.51-5.58 (1H, m), 7.21(2H, d, J=9.4 Hz), 7.28-7.35 (2H, m), 7.40-7.47 (2H, m), 8.66 (1H, d,J=7.2 Hz), 10.70 (1H, s), 11.99 (1H, brs).

Example 1084-(((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)amino)-4-oxobutanoicacid

A solution of(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(80 mg, 0.21 mmol), dihydrofuran-2,5-dione (22.21 mg, 0.22 mmol) and TEA(0.032 mL, 0.23 mmol) in THF (2.0 mL) was stirred at room temperaturefor 3 hr. The reaction mixture was concentrated under reduced pressure,and the obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→50% ethyl acetate/hexane). Theobtained residue was purified by preparative HPLC (C18, mobile phase:water/acetonitrile (containing 0.1% TFA)) to give the title compound(34.5 mg, 0.072 mmol, 34.1%) as a white solid.

MS(API): Calculated 478.6, Found 477.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.30 (9H, s), 2.38-2.48 (4H, m), 3.27 (3H,s), 4.38 (2H, s), 5.56 (1H, d, J=7.6 Hz), 7.22 (2H, d, J=9.4 Hz),7.28-7.34 (2H, m), 7.40-7.47 (2H, m), 8.72 (1H, d, J=7.6 Hz), 10.68 (1H,s), 12.06 (1H, brs).

Example 109(3S)—N-(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(1-methyl-1H-indazol-5-yl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide(Mixture of Two Diastereomers)

(Step 1)

A solution of (1-methyl-1H-indazol-5-yl)boronic acid (1.0 g, 5.68 mmol),glyoxylic acid monohydrate (0.523 g, 5.68 mmol) and diallylamine (0.699mL, 5.68 mmol) in acetonitrile (15 mL) was stirred overnight at 60° C.The precipitate was collected by filtration, and washed with ethylacetate to give 2-(diallylamino)-2-(1-methyl-1H-indazol-5-yl)acetic acid(1.41 g, 4.94 mmol, 87%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ3.04-3.28 (4H, m), 4.03 (3H, s), 4.53 (1H,s), 5.07-5.21 (4H, m), 5.70-5.93 (2H, m), 7.45 (1H, dd, J=8.9, 1.3 Hz),7.62 (1H, d, J=8.7 Hz), 7.70 (1H, s), 8.04 (1H, d, J=0.8 Hz), 12.53 (1H,brs).

(Step 2)

To a solution of 3-fluoro-4-(trimethylsilyl)aniline (300 mg, 1.64 mmol),2-(diallylamino)-2-(l-methyl-1H-indazol-5-yl)acetic acid (514 mg, 1.80mmol), DMAP (220 mg, 1.80 mmol) and DIEA (1.429 mL, 8.18 mmol) in ethylacetate (10 mL) was added T3P (1.926 mL, 3.27 mmol), and the mixture wasstirred at 80° C. for 2 hr. To the reaction mixture were added water andethyl acetate, and the organic layer was separated. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 0→10% ethylacetate/hexane) to give2-(diallylamino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(1-methyl-1H-indazol-5-yl)acetamide(454.4 mg, 1.008 mmol, 61.6%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.29 (9H, d, J=0.8 Hz), 2.91 (2H, dd, J=14.5,7.0 Hz), 3.37 (2H, dd, J=14.5, 5.5 Hz), 4.07 (3H, s), 4.67 (1H, s),5.19-5.33 (4H, m), 5.77-5.97 (2H, m), 7.19-7.25 (1H, m), 7.29-7.49 (4H,m), 7.65 (1H, s), 7.97 (1H, d, J=0.8 Hz), 9.55 (1H, s).

(Step 3)

To a solution of2-(diallylamino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(1-methyl-1H-indazol-5-yl)acetamide(450 mg, 1.00 mmol) and 1,3-dimethylbarbituric acid (327 mg, 2.10 mmol)in THF (10 mL) was added Pd(PPh₃)₄(46.2 mg, 0.04 mmol), and the mixturewas stirred overnight at room temperature under argon gas atmosphere.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography (NH,solvent gradient; 50→100% ethyl acetate/hexane) to give2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(1-methyl-1H-indazol-5-yl)acetamide(313.3 mg, 0.846 mmol, 85%) as a yellow oil.

(Step 4)

To a solution of2-amino-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(1-methyl-1H-indazol-5-yl)acetamide(100 mg, 0.27 mmol), DIEA (0.092 mL, 0.54 mmol) and(S)-5-oxopyrrolidine-3-carboxylic acid (38.3 mg, 0.30 mmol) in DMF (10mL) was added COMU (127 mg, 0.30 mmol) at 0° C., and the mixture wasstirred at room temperature for 5 hr. To the reaction mixture were addedwater and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0→5% MeOH/ethyl acetate), and crystallized from ethylacetate/hexane to give the title compound (52.5 mg, 0.109 mmol, 40.4%)as white crystals.

MS(API): Calculated 481.6, Found 480.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.24 (9H, s), 2.29 (2H, dd, J=18.7, 8.5 Hz),3.12-3.53 (3H, m), 4.02 (3H, s), 5.69 (1H, t, J=6.8 Hz), 7.22-7.37 (2H,m), 7.44-7.59 (3H, m), 7.65 (1H, d, J=8.7 Hz), 7.82 (1H, s), 8.08 (1H,s), 8.85 (1H, t, J=7.7 Hz), 10.57 (1H, d, J=3.8 Hz).

Example 110(3S)—N-(2-((4-(2,2-dimethylpropyl)-3-fluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide(Mixture of Two Diastereomers)

(Step 1)

To a solution of lithium chloride (0.81 g, 19.11 mmol) in THF (10 mL)was added 1.8M tert-butylmagnesium chloride/THF solution (10.61 mL,19.11 mmol), and the mixture was stirred for 15 min under ice-cooling.Then, a solution of lithium chloride (1.785 g, 42.11 mmol) and coprouscyanide (0.646 mL, 21.05 mmol) in THF (20 mL) was added thereto, and themixture was stirred for 10 min under ice-cooling. Then,4-bromo-2-fluorobenzoyl chloride (4.89 g, 20.59 mmol) was added thereto,and the mixture was stirred overnight at room temperature. To thereaction mixture were added aqueous ammonium chloride solution/281aqueous ammonia solution (9:1.50 mL), and the precipitate was removed byfiltration. To the filtrate was added ethyl acetate, and the organiclayer was separated. The organic layer was washed with brine, and driedover magnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give1-(4-bromo-2-fluorophenyl)-2,2-dimethylpropan-1-one (3.54 g, 13.66 mmol,78%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ1.24 (9H, d, J=0.8 Hz), 7.07 (1H, dd, J=8.3,6.8 Hz), 7.27-7.36 (2H, m).

(Step 2)

To a solution of 1-(4-bromo-2-fluorophenyl)-2,2-dimethylpropan-1-one(3.54 g, 13.66 mmol) in TFA (15 mL) was added triethylsilane (5.46 mL,34.15 mmol) at room temperature, and the mixture was stirred for 3 days.TFA was evaporated under reduced pressure, and the residue were addedwater and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (NH, solventgradient; 0→30% ethyl acetate/hexane) to give4-bromo-2-fluoro-1-neopentylbenzene (2.54 g, 10.36 mmol, 76%) as acolorless oil.

¹H NMR (300 MHz, CDCl₃): δ0.91 (9H, d, J=1.1 Hz), 2.49 (2H, d, J=1.5Hz), 6.93-7.10 (1H, m), 7.13-7.24 (2H, m).

(Step 3)

A solution of 4-bromo-2-fluoro-1-neopentylbenzene (2.54 g, 10.36 mmol),diphenylmethanimine (2.253 g, 12.43 mmol), Pd₂(dba)₃ (0.047 g, 0.05mmol), BINAP (0.097 g, 0.16 mmol) and sodium t-butoxide (1.394 g, 14.51mmol) in toluene (20 mL) was stirred at 80° C. for 18 hr. To thereaction mixture was added ethyl acetate, and the insoluble substancewas removed by filtration. The filtrate was concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (solvent gradient; 1→30% ethyl acetate/hexane) to give apale orange oil. To this oil were added MeOH (30 mL), hydroxylaminehydrochloride (1.296 g, 18.65 mmol) and sodium acetate (2.040 g, 24.87mmol), and the mixture was stirred at room temperature for 1 hr. 0.1MAqueous sodium hydroxide solution was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (NH, solvent gradient; 3→97% ethyl acetate/hexane), andthen preparative HPLC (C18, mobile phase: water/acetonitrile (containing0.1% TFA)) to give 3-fluoro-4-neopentylaniline (1.28 g, 7.06 mmol, 68%)as an oil.

¹H NMR (300 MHz, CDCl₃): δ0.89 (9H, d, J=0.8 Hz), 2.41 (2H, d, J=1.5Hz), 3.64 (2H, brs), 6.25-6.46 (2H, m), 6.80-6.94 (1H, m).

(Step 4)

To a solution of 3-fluoro-4-neopentylaniline (200 mg, 1.10 mmol),2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid (304 mg, 1.10mmol), DMAP (148 mg, 1.21 mmol) and DIEA (0.964 mL, 5.52 mmol) in ethylacetate (30 mL) was added T3P (0.974 mL, 1.66 mmol), and the mixture wasstirred at 70° C. for 2 hr. To the reaction mixture were added water andethyl acetate, and the organic layer was separated. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 0→35% ethylacetate/hexane) to give2-(diallylamino)-N-(3-fluoro-4-neopentylphenyl)-2-(4-(methoxymethyl)phenyl)acetamide(307 mg, 0.700 mmol, 63.4%) as a yellow oil.

¹H NMR (300 MHz, CDCl₃): δ0.91 (9H, s), 2.49 (2H, s), 2.87 (2H, dd,J=14.7, 7.2 Hz), 3.34 (2H, dd, J=14.7, 5.3 Hz), 3.40 (3H, s), 4.46 (2H,s), 4.56 (1H, s), 5.17-5.32 (4H, m), 5.75-5.96 (2H, m), 6.98-7.10 (1H,m), 7.10-7.18 (1H, m), 7.26-7.30 (2H, m), 7.31-7.37 (2H, m), 7.46 (1H,dd, J=11.7, 1.9 Hz), 9.44 (1H, s).

(Step 5)

A solution of2-(diallylamino)-N-(3-fluoro-4-neopentylphenyl)-2-(4-(methoxymethyl)phenyl)acetamide(307 mg, 0.70 mmol), Pd(PPh₃)₄ (16.18 mg, 0.01 mmol) and1,3-dimethylbarbituric acid (230 mg, 1.47 mmol) in THF (5 mL) wasstirred at room temperature for 2 days. The reaction mixture wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (NH, solvent gradient; 40-100% ethylacetate/hexane), and the obtained crystals were washed with ethylacetate to give2-amino-N-(3-fluoro-4-neopentylphenyl)-2-(4-(methoxymethyl)phenyl)acetamide(160 mg, 0.446 mmol, 63.8%) as a yellow solid.

¹H NMR (300 MHz, CDCl₃): δ0.90 (9H, s), 1.94 (2H, brs), 2.49 (2H, s),3.37 (3H, s), 4.44 (2H, s), 4.65 (1H, s), 7.01-7.10 (1H, m), 7.13-7.21(1H, m), 7.29-7.36 (2H, m), 7.39-7.45 (2H, m), 7.49 (1H, dd, J=11.7, 1.9Hz), 9.40 (1H, brs).

(Step 6)

A solution of2-amino-N-(3-fluoro-4-neopentylphenyl)-2-(4-(methoxymethyl)phenyl)acetamide(79 mg, 0.22 mmol), DIEA (0.042 mL, 0.24 mmol),(S)-5-oxopyrrolidine-3-carboxylic acid (31.3 mg, 0.24 mmol) and HATU (92mg, 0.24 mmol) in DMF (2 mL) was stirred overnight at room temperature.To the reaction mixture were added water and ethyl acetate, and theorganic layer was separated. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 50→100% ethyl acetate/hexane, 0→15%MeOH/ethyl acetate), and triturated with ethyl acetate/hexane to givethe title compound (110 mg, 0.234 mmol, 106%) as a white powder.

MS(API): Calculated 469.5, Found 468.2 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ0.85 (9H, s), 2.20-2.35 (2H, m), 2.43 (2H,s), 3.12-3.51 (6H, m), 4.38 (2H, s), 5.53-5.64 (1H, m), 7.06-7.17 (1H,m), 7.18-7.25 (1H, m), 7.32 (2H, d, J=7.2 Hz), 7.42-7.59 (4H, m),8.76-8.87 (1H, m), 10.44-10.56 (1H, m).

Example 111(3S)—N-((1R)-2-((4-tert-butyl-3-fluorophenyl)amino)-1-(2,3-dihydro-1-benzofuran-5-yl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

(Step 1)

A solution of (2,3-dihydrobenzofuran-5-yl)boronic acid (680 mg, 4.15mmol), glyoxylic acid monohydrate (382 mg, 4.15 mmol) and diallylamine(0.510 mL, 4.15 mmol) in acetonitrile (15 mL) was stirred overnight at60° C. The reaction mixture was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography (Diol,solvent gradient; 0→10% MeOH/ethyl acetate) to give2-(diallylamino)-2-(2,3-dihydrobenzofuran-5-yl)acetic acid (1.02 g, 3.73mmol, 90%) as a colorless oil.

¹H NMR (300 MHz, DMSO-d₆): δ3.06-3.25 (6H, m), 4.33 (1H, s), 4.44-4.60(2H, m), 5.05-5.24 (4H, m), 5.79 (2H, ddt, J=16.8, 10.4, 6.2 Hz), 6.72(1H, d, J=7.9 Hz), 7.00-7.13 (1H, m), 7.22 (1H, s), 12.37 (1H, brs).

(Step 2)

To a solution of 4-(tert-butyl)-3-fluoroaniline (300 mg, 1.79 mmol),2-(diallylamino)-2-(2,3-dihydrobenzofuran-5-yl)acetic acid (539 mg, 1.97mmol), DMAP (241 mg, 1.97 mmol) and DIEA (1.567 mL, 8.97 mmol) in ethylacetate (10 mL) was added T3P (2.111 mL, 3.59 mmol), and the mixture wasstirred at 80° C. for 2 hr. To the reaction mixture were added water andethyl acetate, and the organic layer was separated. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (solvent gradient; 0→20% ethylacetate/hexane) to giveN-(4-(tert-butyl)-3-fluorophenyl)-2-(diallylamino)-2-(2,3-dihydrobenzofuran-5-yl)acetamide(558.7 mg, 1.322 mmol, 73.7%) as a yellow oil.

(Step 3)

A solution ofN-(4-(tert-butyl)-3-fluorophenyl)-2-(diallylamino)-2-(2,3-dihydrobenzofuran-5-yl)acetamide(550 mg, 1.30 mmol), 1,3-dimethylbarbituric acid (427 mg, 2.73 mmol) andPd(PPh₃)₄ (60.2 mg, 0.05 mmol) in THF (10 mL) was stirred overnight atroom temperature under argon gas atmosphere. The reaction mixture wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (NH, solvent gradient; 50→100% ethylacetate/hexane) to give2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(2,3-dihydrobenzofuran-5-yl)acetamide(352.6 mg, 1.030 mmol, 79%) as a yellow oil.

(Step 4)

To a solution of2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(2,3-dihydrobenzofuran-5-yl)acetamide(100 mg, 0.29 mmol), DIEA (0.100 mL, 0.58 mmol) and(S)-5-oxopyrrolidine-3-carboxylic acid (41.5 mg, 0.32 mmol) in DMF (10mL) was added COMU (138 mg, 0.32 mmol) at 0° C., and the mixture wasstirred at room temperature for 5 hr. To the reaction mixture were addedwater and ethyl acetate, and the organic layer was separated. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0-5% MeOH/ethyl acetate), and crystallized from ethylacetate/hexane to give(3S)—N-(2-((4-(tert-butyl)-3-fluorophenyl)amino)-1-(2,3-dihydrobenzofuran-5-yl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide(mixture of two diastereomers) (51.2 mg, 0.113 mmol, 38.7%) as whitecrystals.

¹H NMR (300 MHz, DMSO-d₆): δ1.29 (9H, s), 2.27 (2H, dd, J=14.2, 8.1 Hz),3.16 (2H, t, J=8.5 Hz), 3.22-3.48 (3H, m), 4.50 (2H, t, J=8.7 Hz),5.42-5.51 (1H, m), 6.75 (1H, d, J=8.3 Hz), 7.13-7.35 (4H, m), 7.44-7.59(2H, m), 8.69 (1H, t, J=7.6 Hz), 10.39 (1H, d, J=3.8 Hz).

(Step 5)

(3S)—N-(2-((4-(tert-Butyl)-3-fluorophenyl)amino)-1-(2,3-dihydrobenzofuran-5-yl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide(mixture of two diastereomers) (45 mg) was subjected to opticalresolution using preparative HPLC (C18, mobile phase: water/acetonitrile(containing 0.1% TEA)). The preparative fraction having a longerretention time was concentrated to give the title compound (13.2 mg) aswhite crystals.

MS(API): Calculated 453.5, Found 452.1 (M−H).

Example 112(3S)—N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(1-methyl-1H-indazol-5-yl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

(3S)—N-(2-((3-Fluoro-4-(trimethylsilyl)phenyl)amino)-1-(1-methyl-1H-indazol-5-yl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide(diastereomer mixture) (45 mg) was subjected to optical resolution usingpreparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1%TEA)). The preparative fraction having a longer retention time wasconcentrated, and crystallized from ethyl acetate/hexane to give thetitle compound (8.7 mg) as white crystals.

MS(API): Calculated 481.6, Found 482.2 (M+H).

Example 113(3R)—N-((1R)-2-((4-tert-butyl-3,5-difluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

(Step 1)

To a solution of 3,5-difluorophenol (17.0 g, 130.68 mmol) in2-methoxy-2-methylpropane (34 mL, 285.43 mmol) was slowly addedzirconium(IV) chloride (15.23 g, 65.34 mmol) while the mixture was keptat 30 to 40° C. The mixture was stirred at room temperature for 2 hr,and then, zirconium(IV) chloride (15.23 g, 65.34 mmol) was slowly addedthereto. The mixture was stirred at room temperature for 2 hr, andpoured into ice and 8N aqueous sodium hydroxide solution (90 mL).Diethyl ether (about 400 mL) was added thereto, and the insolublesubstance was removed by filtration. The filtrate was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give4-(tert-butyl)-3,5-difluorophenol (16.80 g, 90 mmol, 69.0%) as a brownoil.

¹H NMR (300 MHz, CDCl₃): δ1.42 (9H, t, J=2.3 Hz), 5.07-5.26 (1H, m),6.24-6.42 (2H, m)

(Step 2)

To a solution of 4-(tert-butyl)-3,5-difluorophenol (16.8 g, 90.23 mmol)in THF (168 mL) was added sodium hydride (60% in oil, 4.33 g, 108.27mmol) at 0° C., and then,1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(35.5 g, 99.25 mmol) was added thereto. The reaction mixture was stirredat room temperature for 2 hr, and poured into aqueous ammonium chloridesolution. The mixture was extracted with ethyl acetate, and the organiclayer was washed with aqueous sodium hydrogencarbonate solution, anddried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent; hexane) to give4-(tert-butyl)-3,5-difluorophenyl trifluoromethanesulfonate (8.14 g,25.6 mmol, 28.3%) as a pale yellow oil.

¹H NMR (300 MHz, CDCl₃): δ1.46 (9H, t, J=2.3 Hz), 6.80 (2H, d, J=10.2Hz)

(Step 3)

A solution of XANTPHOS (1.407 g, 2.43 mmol), diphenylmethanimine (4.06mL, 24.32 mmol), cesium carbonate (15.85 g, 48.64 mmol),4-(tert-butyl)-3,5-difluorophenyl trifluoromethanesulfonate (5.16 g,16.21 mmol) and Pd₂(dba)₃ (0.742 g, 0.81 mmol) in THE (50 mL) was heatedwith reflux overnight. The reaction mixture was neutralized with aqueoussodium hydrogencarbonate solution. To the reaction mixture was addedethyl acetate, and the organic layer was separated. The organic layerwas washed with brine, and dried over magnesium sulfate, and the solventwas evaporated under reduced pressure. To the obtained residue wereadded THE (50.00 mL) and 6N hydrochloric acid (5 mL, 30 mmol), and themixture was stirred at room temperature for 2 hr. The reaction mixturewas neutralized with aqueous sodium hydrogencarbonate solution, andextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 5→15% ethyl acetate/hexane) to give4-(tert-butyl)-3,5-difluoroaniline (2.100 g, 11.34 mmol, 69.9-) as apale yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ1.33 (9H, t, J=2.1 Hz), 5.46 (2H, s),6.02-6.18 (2H, m).

(Step 4)

T3P (10.11 mL, 17.01 mmol) was added to a solution of2-(diallylamino)-2-(4-methoxyphenyl)acetic acid (3.12 g, 11.34 mmol),4-(tert-butyl)-3,5-difluoroaniline (2.1 g, 11.34 mmol), DIEA (9.90 mL,56.69 mmol) and DMAP (1.524 g, 12.47 mmol) in ethyl acetate (100 mL) atroom temperature, and the mixture was stirred at 70° C. for 15 hr. Tothe reaction mixture were added water and ethyl acetate, and the organiclayer was separated. The organic layer was washed with aqueous sodiumhydrogencarbonate solution and brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0→30% ethyl acetate/hexane) to giveN-(4-(tert-butyl)-3,5-difluorophenyl)-2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetamide(3.16 g, 7.14 mmol, 63.0%) as a pale yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ1.39 (9H, t, J=1.9 Hz), 3.02-3.26 (4H, m),3.28 (3H, s), 4.39 (2H, s), 4.47 (1H, s), 5.12 (2H, s), 5.17 (2H, d,J=4.9 Hz), 5.73-5.95 (2H, m), 7.22-7.35 (4H, m), 7.37-7.45 (2H, m),10.32 (1H, s).

(Step 5)

To a solution ofN-(4-(tert-butyl)-3,5-difluorophenyl)-2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetamide(3.16 g, 7.14 mmol) and 1,3-dimethylbarbituric acid (2.341 g, 15.00mmol) in THF (15 mL) was added Pd(PPh₃)₄(0.330 g, 0.29 mmol), and themixture was stirred overnight at room temperature. The reaction mixturewas concentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (NH, solvent gradient;10→100% ethyl acetate/hexane) to give2-amino-N-(4-(tert-butyl)-3,5-difluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(2.000 g, 5.52 mmol, 77%) as a pale yellow oil.

¹H NMR (300 MHz, DMSO-d₆): δ1.38 (9H, t, J=2.1 Hz), 3.26 (3H, s), 4.37(2H, s), 4.49 (1H, s), 7.23-7.36 (4H, m), 7.42 (2H, d, J=7.9 Hz) (Thefree 3H was not observed.).

(Step 6)

To a solution of2-amino-N-(4-(tert-butyl)-3,5-difluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(2 g, 5.52 mmol) and TEA (1.538 mL, 11.04 mmol) in THF (50 mL) was addedBoc₂O (1.538 mL, 6.62 mmol) at 0° C., and the mixture was stirred for 1hr. To the reaction mixture were added water and ethyl acetate, and theorganic layer was separated. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent gradient; 0→30% ethyl acetate/hexane) to givetert-butyl(2-((4-(tert-butyl)-3,5-difluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(2.180 g, 4.71 mmol, 85%) as white crystals.

¹H NMR (300 MHz, DMSO-d₆): δ1.38 (18H, d, J=2.3 Hz), 3.27 (3H, s), 4.38(2H, s), 5.27 (1H, d, J=6.8 Hz), 7.11-7.25 (2H, m), 7.29 (2H, d, J=7.9Hz), 7.43 (2H, d, J=7.9 Hz), 7.59 (1H, d, J=7.9 Hz), 10.49 (1H, s).

(Step 7)

tert-Butyl(2-((4-(tert-butyl)-3,5-difluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(2.18 g) was subjected to optical resolution using chiral columnchromatography. The preparative fraction having a shorter retention timewas concentrated to give tert-butyl(R)-(2-((4-(tert-butyl)-3,5-difluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(1.02 g, >99.9% ee) as a white solid.

purification condition using chiral column chromatography

column: CHIRALPAK AD(AF001)50 mmID×500 mmL

solvent: hexane/EtOH=850/150

flow rate: 80 mL/min

temperature: 30° C.

detection method: UV 220 nm

(Step 8)

tert-Butyl(R)-(2-((4-(tert-butyl)-3,5-difluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)carbamate(1.02 g, 2.21 mmol) was dissolved in TFA (3 mL, 38.94 mmol), and thesolution was stirred at room temperature for 1 hr. The reaction mixturewas neutralized with aqueous sodium hydrogencarbonate solution, andextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure to give(R)-2-amino-N-(4-(tert-butyl)-3,5-difluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(0.840 g, 2.318 mmol, 105%) as a colorless oil.

¹H NMR (300 MHz, DMSO-d₆): δ1.38 (9H, t, J=1.9 Hz), 3.27 (3H, s),3.29-3.31 (1H, m), 4.38 (2H, s), 4.62 (1H, s), 7.22-7.34 (4H, m), 7.44(2H, d, J=7.9 Hz) (The free 2H was not observed.).

(Step 9)

HATU (126 mg, 0.33 mmol) was added to a solution of(R)-5-oxopyrrolidine-3-carboxylic acid (35.6 mg, 0.28 mmol), DIEA (0.145mL, 0.83 mmol) and(R)-2-amino-N-(4-(tert-butyl)-3,5-difluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(100 mg, 0.28 mmol) in DMF (4 mL) at room temperature, and the mixturewas stirred for 3 hr. The reaction mixture was neutralized with aqueoussodium hydrogencarbonate solution, and extracted with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0→20% MeOH/ethyl acetate), and crystallized from ethylacetate/hexane to give the title compound (75 mg, 0.158 mmol, 57.4%) aswhite crystals.

MS(API): Calculated 473.5, Found 472.1 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ1.38 (9H, s), 2.21-2.31 (2H, m), 3.20-3.30(4H, m), 3.38-3.52 (2H, m), 4.39 (2H, s), 5.53 (1H, d, J=7.2 Hz),7.13-7.26 (2H, m), 7.28-7.35 (2H, m), 7.39-7.49 (2H, m), 7.57 (1H, s),8.83 (1H, d, J=7.2 Hz), 10.62 (1H, s).

Example 114(2R)—N-(4-tert-butyl-3,5-difluorophenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide

(Step 1)

n-BuLi (15.96 mL, 25.53 mmol) was added to diisopropylamine (3.90 mL,27.85 mmol) at −10 to at 0° C., and the mixture was stirred at the sametemperature for 30 min. Then, a solution of 5-methyl-1,2-oxazol-3-ol(1.15 g, 11.61 mmol) in THE (20 mL) was slowly added thereto while themixture was kept at 0° C., and the mixture was stirred at the sametemperature for 1 hr. The reaction mixture was cooled to −78° C., andexcess amount of crushed dry ice was added thereto. The reaction mixturewas stirred at room temperature for 2 hr, and 6N hydrochloric acid wasadded thereto. The mixture was extracted with ethyl acetate (×2). Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure, and theprecipitate was washed with ethyl acetate/hexane to give2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (0.630 g, 4.40 mmol, 37.9%) asa pale yellow solid.

¹H NMR (300 MHz, DMSO-d₆): δ3.73 (2H, s), 5.91 (1H, s), 11.14 (1H, brs),12.76 (1H, brs).

(Step 2)

HATU (99 mg, 0.26 mmol) was added to a solution of DIEA (0.070 mL, 0.40mmol), 2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (31.5 mg, 0.22 mmol) and(R)-2-amino-N-(4-(tert-butyl)-3,5-difluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(72.5 mg, 0.2 mmol) in DMF (5 mL) at room temperature, and the mixturewas stirred for 5 hr. The reaction mixture was neutralized with aqueoussodium hydrogencarbonate solution, and extracted with ethyl acetate. Theorganic layer was washed with brine, and dried over magnesium sulfate,and the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (solventgradient; 0→15% MeOH/ethyl acetate), and crystallized from ethylacetate/hexane to give the title compound (40.0 mg, 0.082 mmol, 41.0%)as a white solid.

MS(API): Calculated 487.5, Found 486.0 (M−H).

¹H NMR (300 MHz, DMSO-d₆): δ1.38 (9H, s), 3.27 (3H, s), 3.71 (2H, s),4.39 (2H, s), 5.55 (1H, d, J=7.2 Hz), 5.84 (1H, s), 7.10-7.26 (2H, m),7.28-7.37 (2H, m), 7.41-7.48 (2H, m), 9.05 (1H, d, J=7.6 Hz), 10.64 (1H,s), 11.11 (1H, brs).

Example 116(2R)—N-(4-tert-butyl-3-fluorophenyl)-2-(((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide

To a solution of(R)-2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(30 mg, 0.09 mmol), DIEA (0.030 mL, 0.17 mmol) and2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (16.30 mg, 0.10mmol) in DMF (2.0 mL) was added HATU (39.7 mg, 0.10 mmol) at roomtemperature, and the mixture was stirred for 2 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate/hexane), and crystallized fromethyl acetate/hexane to give the title compound (23.2 mg, 0.047 mmol,53.6%) as white crystals.

MS(API): Calculated 496.5, Found 497.1 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ1.29 (9H, s), 3.27 (3H, s), 4.39 (2H, s),4.48 (2H, s), 5.54 (1H, d, J=7.9 Hz), 5.61-5.67 (1H, m), 7.15-7.36 (4H,m), 7.42-7.61 (4H, m), 9.11 (1H, d, J=7.6 Hz), 10.52 (1H, s), 11.27 (1H,s).

Example 117(2R)—N-(4-tert-butyl-3-fluorophenyl)-2-(((2,6-dioxopiperidin-4-yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide

To a solution of(R)-2-amino-N-(4-(tert-butyl)-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)acetamide(50 mg, 0.15 mmol), DIEA (0.050 mL, 0.29 mmol) and2-(2,6-dioxopiperidin-4-yl)acetic acid (27.3 mg, 0.16 mmol) in DMF (2.0mL) was added HATU (66.2 mg, 0.17 mmol) at room temperature, and themixture was stirred for 2 hr. To the reaction mixture were added waterand ethyl acetate, and the organic layer was separated. The organiclayer was washed with brine, and dried over magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (solvent; ethylacetate/hexane), and crystallized from ethyl acetate/hexane to give thetitle compound (21.9 mg, 0.044 mmol, 30.3%) as white crystals.

MS(API): Calculated 497.6, Found 498.2 (M+H).

¹H NMR (300 MHz, DMSO-d₆): δ1.29 (9H, s), 2.20-2.40 (5H, m), 3.27 (3H,s), 3.30 (2H, s), 4.38 (2H, s), 5.57 (1H, d, J=7.2 Hz), 7.16-7.35 (4H,m), 7.40-7.54 (3H, m), 8.75 (1H, d, J=7.2 Hz), 10.46 (1H, s), 10.71 (1H,s).

The compounds of Examples 115, 118 to 126, 128 to 154, 156 to 214, 216to 253, 255 to 382, 384 to 402, 406, 407 and 409 to 418 were synthesizedin the same manner as in Examples 1 to 117.

Example 419(2R)—N-(4-tert-butyl-3,5-difluorophenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)-2-(1-methyl-1H-indazol-5-yl)acetamide

(Step 1)

T3P (6.35 ml, 10.80 mmol) was added to a solution of4-(tert-butyl)-3,5-difluoroaniline (1.0 g, 5.40 mmol),2-(diallylamino)-2-(1-methyl-1H-indazol-5-yl)acetic acid (1.695 g, 5.94mmol), DMAP (0.726 g, 5.94 mmol) and DIEA (4.71 ml 27.0 mmol) in ethylacetate (30 ml), and the mixture was stirred at 80° C. for 2 hr. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, and dried overmagnesium sulfate, and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate/hexane) to giveN-(4-(tert-butyl)-3,5-difluorophenyl)-2-(diallylamino)-2-(1-methyl-1H-indazol-5-yl)acetamide(1.37 g, 3.03 mmol, 56.1%) as a grayish white solid.

MS(API): Calculated 452.5, Found 453.2 (M+H).

(Step 2)

A solution ofN-(4-(tert-butyl)-3,5-difluorophenyl)-2-(diallylamino)-2-(1-methyl-1H-indazol-5-yl)acetamide(1.37 g, 3.03 mmol) and 1,3-dimethylbarbituric acid (0.993 g, 6.36 mmol)in THE (25 ml) was degassed, and Pd(PPh₃)₄(0.140 g, 0.12 mmol) was addedthereto. The mixture was stirred overnight at room temperature underargon gas atmosphere. The reaction mixture was concentrated underreduced pressure, and the obtained residue was purified by silica gelcolumn chromatography (NH, solvent gradient; 50→100% ethylacetate/hexane) to give crude2-amino-N-(4-(tert-butyl)-3,5-difluorophenyl)-2-(1-methyl-1H-indazol-5-yl)acetamide(1.15 g, 3.09 mmol, 102%) as a pale yellow oil.

MS(API): Calculated 372.4, Found 371.2 (M−H).

(Step 3)

To a solution of the crude2-amino-N-(4-(tert-butyl)-3,5-difluorophenyl)-2-(1-methyl-1H-indazol-5-yl)acetamide(1.05 g, 2.82 mmol) and TEA (0.786 ml, 5.64 mmol) in THF (20 ml) wasadded Boc₂O (0.786 ml, 3.38 mmol) at room temperature, and the mixturewas stirred at room temperature for 2 hr. To the reaction mixture wereadded water and ethyl acetate, and the organic layer was separated. Theorganic layer was dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent; ethyl acetate/hexane) to givetert-butyl(2-((4-(tert-butyl)-3,5-difluorophenyl)amino)-1-(1-methyl-1H-indazol-5-yl)-2-oxoethyl)carbamate(1.36 g, 2.88 mmol, 102%) as a white solid.

MS(API): Calculated 472.5, Found 471.3 (M−H).

(Step 4)

tert-Butyl(2-((4-(tert-butyl)-3,5-difluorophenyl)amino)-1-(1-methyl-1H-indazol-5-yl)-2-oxoethyl)carbamatewas subjected to optical resolution using chiral column chromatography.The preparative fraction having a shorter retention time wasconcentrated to give tert-butyl(S)-2-((4-(tert-butyl)-3,5-difluorophenyl)amino)-1-(1-methyl-1H-indazol-5-yl)-2-oxoethyl)carbamate(0.43 g, >99% ee), and the preparative fraction having a longerretention time was concentrated to give tert-butyl(R)-2-((4-(tert-butyl)-3,5-difluorophenyl)amino)-1-(1-methyl-1H-indazol-5-yl)-2-oxoethyl)carbamate(0.43 g, >99% ee).

purification condition using chiral column chromatography

column: CHIRALCEL IA(QK001)50 mmID×500 mmL

solvent: hexane/2-propanol=600/400

flow rate: 80 mL/min

temperature: 30° C.

detection method: UJV 220 nm

(Step 5)

4N Hydrogen chloride/ethyl acetate (4.5 ml, 18.0 mmol) was added to asolution of tert-butyl(R)-(2-((4-(tert-butyl)-3,5-difluorophenyl)amino)-1-(1-methyl-1H-indazol-5-yl)-2-oxoethyl)carbamate(430 mg, 0.91 mmol) in ethyl acetate (6.0 ml), and the mixture wasstirred at room temperature for 5 hr. The precipitate was collected byfiltration with ethyl acetate to give(R)-2-amino-N-(4-(tert-butyl)-3,5-difluorophenyl)-2-(1-methyl-1H-indazol-5-yl)acetamidehydrochloride (381.0 mg, 0.932 mmol, 102%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.37 (9H, t, J=1.9 Hz), 4.05 (3H, s), 5.40(1H, d, J=4.9 Hz), 7.22-7.35 (2H, m), 7.62-7.69 (1H, m), 7.70-7.77 (1H,m), 8.04 (1H, s), 8.16 (1H, s), 8.92 (3H, d, J=2.6 Hz), 11.57 (1H, s).

(Step 6)

HATU (112 mg, 0.29 mmol) was added to a solution of(R)-2-amino-N-(4-(tert-butyl)-3,5-difluorophenyl)-2-(1-methyl-1H-indazol-5-yl)acetamidehydrochloride (100 mg, 0.24 mmol), DIEA (0.084 ml, 0.49 mmol) and2-(3-hydroxy-1,2-oxazol-5-yl)acetic acid (42.0 mg, 0.29 mmol) in DMF(2.0 ml) at room temperature, and the mixture was stirred at roomtemperature for 2 hr. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith brine, and dried over magnesium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (solvent gradient; 5→50% ethylacetate/hexane) to give the title compound (19.2 mg, 0.039 mmol, 15.81)as a pale yellow solid.

¹H NMR (300 MHz, DMSO-d₆): δ1.37 (9H, s), 3.71 (2H, s), 4.03 (3H, s),5.64 (1H, d, J=7.6 Hz), 5.85 (1H, s), 7.20 (2H, d, J=12.5 Hz), 7.48 (1H,d, J=8.7 Hz), 7.66 (1H, d, J=8.7 Hz), 7.82 (1H, s), 8.08 (1H, s), 9.06(1H, d, J=7.6 Hz), 10.62 (1H, s), 11.08 (1H, brs).

The compounds described in Examples 1 to 126, 128 to 154, 156 to 214,216 to 253, 255 to 382, 384 to 402, 406, 407 and 409 to 419 are asfollows (Table 1-1 to Table 1-42).

TABLE 1-1 Ex. MS No. IUPAC NAME Structure Salt (Found)  1N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-(((6-oxopyrimidin-1(6H)-yl)acetyl) amino)-2-(tetrahydro-2H-pyran-4-yl)acetamide

477.1 (M − H)  2 N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(((5-methyl- (1,3,4-oxadiazol-2-yl)acetyl)amino)-2-(tetrahydro-2H- pyran-4-yl)acetamide

465.1 (M − H)  3 N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)- 2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3- hydroxy-1,2-oxazole-5- carboxamide

451.9 (M − H)  4 N-(1-(4,4-difluorocyclohexyl)- 2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)- 2-oxoethyl)-3-hydroxy-1,2-oxazole-5-carboxamide

468.1 (M − H)  5 (3S)-N-(1-(4,4-difluorocyclohexyl)- 2-((3-fluoro-4-(trimethylsilyl)phenyl) amino)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

468.1 (M − H)  6 N-(2-((3,5-difluoro-4- (trimethylsilyl)phenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran- 4-yl)ethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

466.0 (M − H)  7 (3S)-N-((1R)-2-((4-tert- butyl-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)- 2-oxoethyl)-5-oxopyrrolidine- 3-carboxamide

452.1 (M − H)  8 N-(2-((4-tert-butyl-3- fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2- oxoethyl)-2-oxo-1,3-oxazolidine- 5-carboxamide(mixture of two diastereomers)

454.1 (M − H)  9 N-((1R)-2-((4-tert-butyl- 3-chlorophenyl)amino)-2-oxo-1-(tetrahydro-2H- pyran-4-yl)ethyl)-3,3,3- trifluoropropanamide

433.0 (M − H) 10 N-((1R)-2-((4-tert-butyl- 3-chlorophenyl)amino)-2-oxo-1-(tetrahydro-2H- pyran-4-yl)ethyl)-3,3,3-trifluoro-2-hydroxypropanamide (single optical isomer)

448.9 (M − H)

TABLE 1-2 Ex. MS No IUPAC NAME Structure Salt (Found) 11N-((1R)-2-((4-tert-butyl- 3-chlorophenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran- 4-yl)ethyl)-3,3,3-trifluoro-2-hydroxypropanamide (single optical isomer)

448.9 (M − H) 12 3-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-1,2- oxazole-5-carboxamide

452.0 (M − H) 13 N-(1-(4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl)amino) ethyl)-5-oxopyrrolidine-3- carboxamide(mixture of four optical isomers)

438.2 (M − H) 14 3-hydroxy-N-((1R)-1- (4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-1,2-oxazole-5-carboxamide

452.0 (M − H) 15 N-(2-((3-fluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

470.0 (M − H) 16 2-(4-methoxyphenyl)-2- (((6-oxo-1,6-dihydropyridin-3-yl)acetyl)amino)-N-(4- (trimethylsilyl)phenyl)acetamide

464.2 (M + H) 17 N-(2-((3,5-difluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2- oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

490.1 (M + H) 18 2-(4-methoxyphenyl)- 2-(((3-methyl-1,2-oxazol-5-yl)acetyl)amino)-N-(4- (trimethylsilyl)phenyl)acetamide

452.2 (M + H) 19 2-(4-methoxyphenyl)- 2-(((1-methyl-1H-pyrazol-3-yl)acetyl)amino)-N-(4- (trimethylsilyl)phenyl)acetamide

451.1 (M + H) 20 2-(4-methoxyphenyl)- 2-(((1-methyl-1H-pyrazol-4-yl)acetyl)amino)-N-(4-( trimethylsilyl)phenyl)acetamide

451.1 (M + H)

TABLE 1-3 Ex. MS No. IUPAC NAME Structure Salt (Found) 21N-(2-((2,5-diflouro-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2- oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

488.0 (M − H) 22 2-(4-(methoxymethyl) phenyl)-2-(((1-methyl-1H-pyrazol-4-yl)acetyl)amino)-N-(4- (trimethylsilyl)phenyl)acetamide

465.1 (M + H) 23 N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)- 1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy- N-methyl-1,2-oxazole-5- carboxamide

488.0 (M − H) 24 N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1- (4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl- 1,2-oxazole-5-carboxamide

470.0 (M − H) 25 N-((1R)-2-((2,5-difluoro-4-(trimethylsilyl)phenyl)amino)- 1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy- N-methyl-1,2-oxazole-5- carboxamide

488.0 (M − H) 26 N-(2-((3-cyano-4- (trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2- oxoethyl)-5-oxopyrrolidine- 3-carboxamide(mixture of four optical isomers)

479.2 (M + H) 27 N-(2-((3-cyano-4-(trimethylsilyl) phenyl)amino)-1-(4-methoxyphenyl)-2- oxoethyl)-5-oxopyrrolidine-3- carboxamide (mixture offour optical isomers)

463.0 (M − H) 28 N-(2-((3-fluoro-4-(trimethylsilyl) phenyl)amino)-1-(4-methoxyphenyl)-2- oxoethyl)-5-oxopyrrolidine-3- carboxamide (mixture offour optical isomers)

456.0 (M − H) 29 N-(2-((3-fluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 3-hydroxypyrrolidine-1- carboxamide (mixtureof four optical isomers)

460.3 (M + H) 30 N-(2-((3-fluoro-4-(trimethylsilyl) phenyl)amino)-1-(4-(methoxyphenyl)-2- oxoethyl)-3-hydroxyazetidine-1- carboxamide

446.2 (M + H)

TABLE 1-4 Ex. MS No. IUPAC NAME Structure Salt (Found) 31N-(2-((3-fluoro-4- (trimethylsilyl) phenyl)amino)-1-(4-(methoxymethyl)phenyl)- 2-oxoethyl)-3-hydroxy-N- methyl-1,2-oxazole-5-carboxamide

484.1 (M − H) 32 N-(2-((3-fluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)- 2-oxoethyl)-5-oxopyrrolidine- 3-carboxamide(mixture of four optical isomers)

470.2 (M − H) 33 N-(2-((3-fluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl) phenyl)-2-oxoethyl)-3- hydroxypyrrolidine-1- carboxamide(mixture of four optical isomers)

474.2 (M + H) 34 N-(2-((3-fluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl) phenyl)-2-oxoethyl)-3- hydroxyazetidine-1-carboxamide

460.3 (M + H) 35 N-(3-fluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((5-methyl-1,3,4-oxadiazol- 2-yl)acetyl)amino)acetamide

485.2 (M + H) 36 N-(3-fluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

497.2 (M + H) 37 N-(2-((3,5-difluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2- oxoethyl)-5-oxopyrrolidine-3- carboxamide

474.1 (M − H) 38 N-(2-((3,5-difluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)- 2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

502.1 (M − H) 39 N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-(((3-hydroxy-1,2-oxazol-5- yl)acetyl)amino)-2-(4- (methoxymethyl)phenyl)acetamide

504.2 (M + H) 40 N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

513.1 (M − H)

TABLE 1-5 Ex. MS No IUPAC NAME Structure Salt (Found) 41N-(2-((3,5-difluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2- oxoethyl)-3-hydroxyazetidine-1- carboxamide

464.1 (M + H) 42 N-(2-((2,5-difluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2- oxoethyl)-5-oxopyrrolidine-3- carboxamide (mixtureof four optical isomers)

474.1 (M − H) 43 N-(2-((2,5-difluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)- 2-oxoethyl)-3-hydroxy-N- methyl-1,2-oxazole-5-carboxamide

502.2 (M − H) 44 N-(2,5-difluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)amino)acetamide

503.2 (M + H) 45 N-(2,5-difluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

515.2 (M + H) 46 N-(2,5-difluoro-4- (trimethylsilyl)phenyl)-2-((1H-indazol-1-yl)acetyl)amino)-2-(4- methoxyphenyl)acetamide

523.2 (M + H) 47 N-(2,5-difluoro-4- (trimethylsilyl)phenyl)-2-((1H-indazol-1-yl)acetyl)amino)-2-(4- (methoxymethyl)phenyl)acetamide

537.2 (M + H) 48 N-(2-((3-chloro-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

486.1 (M − H) 49 (3S)-N-(1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine- 3-carboxamide

470.2 (M − H) 50 (3S)-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)- 1-(4-methoxyphenyl)-2-oxoethyl)-5-oxopyrrolidine- 3-carboxamnide

458.2 (M + H)

TABLE 1-6 Ex. MS No. IUPAC NAME Structure Salt (Found) 51(3S)-N-((1R)-2-((2,5-difluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2- oxoethyl)-5-oxopyrrolidine- 3-carboxamide

490.2 (M + H) 52 (3S)-N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine- 3-carboxamide

488.2 (M − H) 53 (2R)-N-(3-fluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

497.2 (M + H) 54 (3R)-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine- 3-carboxamide

470.1 (M − H) 55 (3R)-N-((1R)-2-((2,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- ((methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine- 3-carboxamide

488.1 (M − H) 56 (2R)-N-(2,5-difluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2- (((5-methyl-1,3,4-oxadiazoi-2-yl)acetyl)amino)acetamide

503.2 (M + H) 57 (2R)-N-(2,5-difluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

515.2 (M + H) 58 (2R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

513.1 (M − H) 59 ((2R)-2-(((2,4-dioxo- 3,4-dihydropyrimidin-1(2H)-yl)acetyl)amino)-N-(3- fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide

513.1 (M + H) 60 (2R)-2-(((2,6-dioxo- 3,6-dihydropyrimidin-1(2H)-yl)acetyl)amino)-N-(3- fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide

513.1 (M + H)

TABLE 1-7 Ex. MS No. IUPAC NAME Structure Salt (Found) 61(2R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2- (((3-methyl-6-oxopyridazin-1(6H)-yl)acetyl)amino)acetamide

529.2 (M + H) 62 (2R)-2-(((2,5-dioxoimidazolidin- 1-yl)acetyl)amino)-N-(3-fluoro-4-(trimethylsilyl) phenyl)-2-(4-(methoxymethyl)phenyl)acetamide

501.2 (M + H) 63 (2R)-N-(3-fluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((4-oxopyridazin-1(4H)-yl)acetyl)amino)acetamide

495.1 (M − H) 64 ((3S)-N-(1R)-2-(3-fluoro-4-(trimethylsilyl)phenyl)amino)- 1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxypyrrolidine -1-carboxamide

460.3 (M + H) 65 (3S)-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3- hydroxypyrrolidine-1-carboxamide

474.2 (M + H) 66 (3R)-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3- hydroxypyrrolidine-1-carboxamide

474.2 (M + H) 67 (2R)-N-(3-fluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((5-methyl-1,3,4-oxadiazol-(2-yl)acetyl)amino)acetamide

483.2 (M − H) 68 (3R)-N-((1R)-2-((3,5-difiuoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine- 3-carboxamide

488.2 (M − H) 69 N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1- (4-(methoxymethyl)phenyl)-2-oxoethyl)-3- hydroxyazetidine-1-carboxamide

460.3 (M + H) 70 (3R)-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)- 1-(4-methoxyphenyl)-2-oxoethyl)-5-oxopyrrolidine-3- carboxamnide

458.2 (M + H)

TABLE 1-8 Ex. MS No. IUPAC NAME Structure Salt (Found) 71(3R)-N-((1R)-2-((3-fluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2- oxoethyl)-3-hydroxypyrrolidine- 1-carboxamide

460.3 (M + H) 72 N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-3- hydroxypropanamide

451.2 (M + H) 73 3-cyano-N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)propanamide

458.1 (M − H) 74 (2R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)amino)acetamide

501.2 (M − H) 75 (2R)-N-(3-fluoro-4- (trimethylsilyl)phenyl)-2-(((3-hydroxy-1,2-oxazol- 5-yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide

486.2 (M + H) 76 (2R)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-(((3-(hydroxy-1,2-oxazol-5- yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide

502.1 (M − H) 77 N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxy-N- methyl-1,2-oxazole-5-carboxamide

502.1 (M − H) 78 (2R)-N-(3-fluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((4-oxopyridin-1(4H)-yl)acetyl)amino)acetamide

496.2 (M + H) 79 N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1- (4-(methoxymethyl)phenyl)-2-oxoethyl)propanamide

417.2 (M + H) 80 N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1- (4-(methoxymethyl)phenyl)-2-oxoethyl)-3- (methylsulfonyl)propanamide

495.2 (M + H)

TABLE 1-9 Ex. MS No IUPAC NAME Structure Salt (Found) 81(2R)-N-(3-fluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2- (((methylsulfonyl)acetyl) amino)acetamide

481.2 (M + H) 82 N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxy-1,2- oxazole-5-carboxamide

490.1 (M + H) 83 N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1- (4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-1,2- oxazole-5-carboxamide

458.1 (M + H) 84 2,2-difluoro-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)cyclopropanecarboxamide (mixture of two diastereomers)

465.1 (M + H) 85 (2R)-N-(3-fluoro-4- (trimethylsilyl)phenyl)-2-(glycoloylamino)-2-(4- (methoxymethyl)phenyl)acetamide

419.1 (M + H) 86 N2-acetyl-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)glycinamide

460.3 (M + H) 87 1-acetyl-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)piperidine-4- carboxamide

512.2 (M − H) 88 N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1- (4-(methoxymethyl)phenyl)-2-oxoethyl)tetrahydro-2H- pyran-4-carboxamide

473.2 (M + H) 89 (2R)-N-(3-fluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)- 2-((tetrahydro-2H-pyran-4-yl)acetyl)amino)acetamide

487.2 (M + H) 90 (2R)-2-((ethylcarbamoyl) amino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4- (methoxymethyl)phenyl)acetamide

432.1 (M + H)

TABLE 1-10 Ex. MS No IUPAC NAME Structure Salt (Found)  913,3-difluoro-N-((1R)-2-((3-fluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2- oxoethyl)cyclobutanecarboxamide

479.2 (M + H)  92 4,4-difluoro-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)propanamide

467.2 (M + H)  93 3,3,3-trifluoro-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)propanamide

471.1 (M + H)  94 4,4,4-trifluoro-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)butanamide

485.2 (M + H)  95 (3R)-3-fluoro-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)pyrrolidine-1- carboxamide

476.2 (M + H)  96 (3S)-3-fluoro-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)pyrrolidine-1- carboxamide

476.3 (M + H)  97 (2R)-N-(3-fluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)- 2-((morpholin-4- ylacetyl)amino)acetamide

HCl 488.2 (M − HCl + H)  98 N-((1R)-2-((2,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)-3-hydroxy-1,2- oxazole-5-carboxamide

490.1 (M + H)  99 N-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1- (4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-1,2- oxazole-5-carboxamide

476.2 (M + H) 100 (2R)-N-(4-tert-butyl- 3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

481.2 (M + H)

TABLE 1-11 Ex. MS No. IUPAC NAME Structure Salt (Found) 101(3S)-N-((1R)-2-((4-tert-butyl- 3-fluorophenyl)amino)-1-(4-(methoxymethyl) phenyl)-2-oxoethyl)-5- oxopyrrolidine-3-carboxamide

454.1 (M − H) 102 (3R)-N-((1R)-2-((4-tert- butyl-3-fluorophenyl)amino)-1-(4-(methoxymethyl) phenyl)-2-oxoethyl)-5- oxopyrrolidine-3-carboxamide

454.1 (M − H) 103 4-(((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)amino)-2,2- dimethyl-4-oxobutanoic acid

507.2 (M + H) 104 (3S)-N-(2-((4-tert-butyl- 3-chlorophenyl)amino)-1-(4-(methoxymethyl)phenyl)- 2-oxoethyl)-5-oxopyrrolidine- 3-carboxamide

470.1 (M − H) 105 (2R)-N-(4-tert-butyl- 3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)amino)acetamide

469.2 (M + H) 106 (2R)-N-(4-tert-butyl-3- fluorophenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)-2-(4- (methoxymethyl)phenyl)acetamide

470.2 107 5-(((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)amino)-5- oxopentanoic acid

493.2 (M + H) 108 4-(((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)amino)-4- oxobutanoic acid

477.1 (M − H) 109 (35)-N-(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1- (1-methyl-1H-indazol-5-yl)-2-oxoethyl)-5- oxopyrrolidine-3-carboxamide (mixture of twodiastereomers)

480.1 (M − H) 110 (3S)-N-(2-((4-(2,2-dimethylpropyl)-3-fluorophenyl)amino)-1- (4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine- 3-carboxamide (mixture of two diastereomers)

468.2 (M − H)

TABLE 1-12 Ex. MS No. IUPAC NAME Structure Salt (Found) 111(3S)-N-(2-((4-tert-butyl- 3-fluorophenyl)amino)-1-(2,3-dihydro-1-benzofuran- 5-yl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

452.1 (M − H) 112 (3S)-N-(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1- (1-methyl-1H-indazol-5-yl)-2-oxoethyl)-5- oxopyrrolidine-3-carboxamide

482.2 (M + H) 113 (3R)-N-((1R)-2-((4-tert-butyl-3,5-difluorophenyl)amino)-1- (4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine- 3-carboxamide

472.1 (M − H) 114 (2R)-N-(4-tert-butyl- 3,5-difluorophenyl)-2-(((3-hydroxy-1,2-oxazol- 5-yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide

486.0 (M − H) 115 (3S)-N-((1R)-2-((4-(2,2-dimethylpropyl)-3-fluorophenyl)amino)-1- (4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine- 3-carboxamide

468.1 (M − H) 116 (2R)-N-(4-tert-butyl-3- fluorophenyl)-2-(((2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide

497.1 (M + H) 117 (2R)-N-(4-tert-butyl-3-f luorophenyl)-2-(((2,6-dioxopiperidin-4-yl) acetyl)amino)-2-(4- (methoxymethyl)phenyl)acetamide

498.2 (M + H) 118 3-cyano-N-(2-oxo-1- (tetrahydro-2H-pyran-4-yl)-2-((4-(trimethylsilyl)phenyl) amino)ethyl)propanamide

386.1 (M − H) 119 N-(2-((3,5-diflouro-4-(trimethylsilyl)phenyl)amino)-2- oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3-hydroxy- 1,2-oxazole-5-carboxamide

452.0 (M − H) 120 (3S)-N-((1S)-2-((4-tert- butyl-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)- 2-oxoethyl)-5- oxopyrrolidine-3-carboxamide

452.1 (M − H)

TABLE 1-13 Ex. MS No. IUPAC NAME Structure Salt (Found) 1215-(((1R)-2-((4-tert-butyl- 3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)- 2-oxoethyl)amino)-5- oxopentanoic acid

455.1 (M − H) 122 (3S)-N-(1S)-2-(4-tert- butyl-3-chlorophenyl)amino)-(2-oxo-1-(tetrahydro- 2H-pyran-4-yl)ethyl)-5-oxopyrrolidine-3-carboxamide

434.0 (M − H) 123 (3S)-N-(1R)-2-(4-tert- butyl-3-chlorophenyl)amino)-2-oxo-1-(tetrahydro- 2H-pyran-4-yl)ethyl)-5-oxopyrrolidine-3-carboxamnide

434.1 (M − H) 124 (2Z)-N″5″-((1R)-2-((4-tert-butyl-3-fluorophenyl)amino)-1- (4,4-difluorocyclohexyl)-2-foxoethyl)-3-hydroxypent- 2-enediamide

470.4 (M + H) 125 (2R)-N-(4-tert-butyl- 3-fluorophenyl)-2-(4,4-difluorocyclohexyl)-2- (((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)acetamide

466.0 (M − H) 126 (3S)-N-(2-((4-tert-butyl- 3-fluorophenyl)amino)-2-oxo-1-(1-(2,2,2-trifluoroethyl) piperidin-4-yl)ethyl)-5-oxopyrrolidine-3- carboxamide

501.2 (M + H) 128 (2R)-N-(4-tert-butyl-3- chlorophenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)- 2-(tetrahydro-2H-pyran- 4-yl)acetamide

448.0 (M − H) 129 (3S)-N-((1R)-2-((4-tert- butyl-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-3-hydroxypyrrolidine-1-carboxamide

454.1 (M − H) 130 (3S)-N-((1R)-2-((4-tert- butyl-3-chlorophenyl)amino)-2-oxo-1-(tetrahydro- 2H-pyran-4-yl)ethyl)-3-hydroxypyrrolidine-1-carboxamide

436.1 (M − H)

TABLE 1-14 Ex. MS No. IUPAC NAME Structure Salt (Found) 131N-(2-((4-tert-butyl-3- fluorophenyl)amino)-1-(1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-2-oxoethyl)-3- hydroxy-1,2-oxazole-5-carboxamide

465.9 (M − H) 132 (3S)-N-(2-((4-tert-butyl-3- fluorophenyl)amino)-1-(4,4-difluoro-1-hydroxycyclohexyl)- 2-oxoethyl)-5- oxopyrrolidine-3-carboxamide (mixture of two diastereomers)

468.0 (M − H) 133 N-(4-tert-butyl-3- fluorophenyl)-2-(1,1-dioxidotetrahydro-2H- thiopyran-4-yl)-2-((1H-indazol-1-ylacetyl)amino)acetamide

515.1 (M + H) 134 N-(4-tert-butyl-3-fluorophenyl)- 2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)acetamide

515.2 (M + H) 135 N-((1R)-2-((4-tert-butyl- 3-chlorophenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran- 4-yl)ethyl)-3,3,3-trifluoro- 2-hydroxy-2-(trifluoromethyl)propanamide

517.0 (M − H) 136 N-((1R)-2-((4-tert-butyl- 3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)- 2-oxoethyl)-1- hydroxycyclopropanecarboxamide

425.1 (M − H) 137 (2S)-N-((1R)-2-((4-tert- butyl-3-chlorophenyl)amino)-2-oxo-1-(tetrahydro- 2H-pyran-4-yl)ethyl)-2- hydroxypropanamide

397.1 (M + H) 138 (2S)-N-((1R)-2-((4-tert- butyl-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-2- hydroxypropanamide

413.1 (M − H) 139 (2S)-N-((1R)-2-((4-tert-butyl-3,5-difluorophenyl)amino)-2- oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)-2-hydroxypropanamide

397.1 (M − H) 140 N-(2-((4-tert- butylphenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)- N-methyl-2-furamide

419.2 (M − H)

TABLE 1-15 Ex. No. IUPAC NAME Structure Salt MS (Found) 141N-(2-((4-tert-butylphenyl) amino)-1-(4- (methoxyphenyl)-2-oxoethyl)-N-methyl- 1,2-oxazole-5- carboxamide

420.1 (M − H) 142 6-acetamido-N-(2-((4-tert- butylphenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)- N-methylnicotinamide

489.1 (M + H) 143 (N-(2-((4-tert-butylphenyl) amino)-1-(4-methoxyphenyl)-2- oxoethyl)-6-cyano-N- methylnicotinamide

455.1 (M − H) 144 N-(2-((4-tert-butylphenyl) amino)-1-(4-methoxyphenyl)-2- oxoethyl)-3-hydroxy- N-methyl-1,2-oxazole-5-carboxamide

438.1 (M + H) 145 N-(2-((4-tert-butylphenyl) amino)-1-(4-(methoxyphenyl)-2- oxoethyl)-N-methyl- 1H-imidazole- 4-carboxamide

421.1 (M + H) 146 N-(2-((4-tert-butylphenyl) amino)-1-(4-methoxyphenyl)- 2-oxoethyl)- N-methyl-5- oxopyrrolidine-3- carboxamide(mixture of four optical isomers)

436.1 (M − H) 147 N-(2-((4-tert-butylphenyl) amino)-1-(4-(methoxyphenyl)-2- oxoethyl)-4-hydroxy-N- methylbenzamide

445.1 (M − H) 148 N-(2-((4-tert-butylphenyl) amino)-1-(4-(methoxyphenyl)-2- oxoethyl)-N-methyl-6- oxopiperidine-3-carboxamide(mixture of four optical (isomers)

452.1 (M + H) 149 N-(2-((4-tert-butyl- phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 3-hydroxy-1,2-oxazole-5- carboxamide

424.1 (M + H) 150 N-(2-((4-tert-butylphenyl) amino)-1-(4-(methoxyphenyl)-2- oxoethyl)-N-methyl-4- oxocyclohexanecarboxamide

451.2 (M + H)

TABLE 1-16 Ex. No. IUPAC NAME Structure Salt MS (Found) 151N-(2-((4-tert-butylphenyl) amino)-1-(4- methoxyphenyl)-2-oxoethyl)-N-methyltetrahydro- 2H-thiopyran- 4-carboxamide

453.2 (M − H) 152 N-(2-((4-tert-butylphenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)- N-methyltetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide

485.2 (M − H) 153 N-(2-((4-tert-butylphenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)- N-methyltetrahydro-2H-thiopyran-4-carboxamide 1-oxide

471.2 (M + H) 154 N-(2-((4-tert-butylphenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 5-methoxy-N-methyl-1H-pyrazole-3-carboxamide

451.1 (M + H) 156 N-(2-((4-(1,1,1,3,3,3- hexafluoro-2-hydroxypropan-2-yl)phenyl)amino)-1-(4- methoxyphenyl)-2-oxoethyl)-N-methyl-5-oxopyrrolidine- 3-carboxamide (mixture of four optical isomers)

546.0 (M − H) 157 N-(2-((4-(2,2-dimethylpropyl) phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)- N-methyl-5- oxopyrrolidine-3-carboxamide(mixture of four optical fisomers)

452.2 (M + H) 158 N-(2-((4-tert-butylphenyl) amino)-1-(4-methoxyphenyl)-2- oxoethyl)-5-oxopyrrolidine-3- carboxamide (mixture offour optical isomers)

424.2 (M + H) 159 4-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N- methylthiophene- 2-carboxamide

467.2 (M − H) 160 2-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-1H-imidazole-4-carboxamide

451.2 (M − H) 161 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-2- oxoimidazolidine-4-carboxamide (mixture of four optical isomers)

453.2 (M − H)

TABLE 1-17 Ex. No. IUPAC NAME Structure Salt MS (Found) 1623-hydroxy-N-(1-(4- methoxyphenyl)- 2-oxo-2-((4- (trimethylsilyl)phenyl)amino)ethyl)- N-methyl-1H-1,2,4- triazole-5-carboxamide

452.2 (M − H) 163 2-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)- N,5-dimethyl-1,3-oxazole-4-carboxamide

466.2 (M − H) 164 2-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)- N,4-dimethyl-1,3-thiazole-5-carboxamide

482.2 (M − H) 165 6-fluoro-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N- methylnicotinamide

464.2 (M − H) 166 6-amino-N-(1-(4- methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N- methylnicotinamide

461.3 (M − H) 167 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-2-oxoindoline-5-carboxamide

500.3 (M − H) 168 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-2-oxoindoline-6-carboxamide

500.3 (M − H) 169 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)- N-methyl-3-oxo-3,4-dihydro-2H-1,4- benzoxazine-7- carboxamide

516.3 (M − H) 170 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-1H-pyrrolo[2,3-b]pyridine- 5-carboxamide

485.3 (M − H) 171 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-1H-pyrazolo[3,4-b]pyridine- 3-carboxamide

486.3 (M − H)

TABLE 1-18 Ex. No. IUPAC NAME Structure Salt MS (Found) 172N-(1-(4-methoxyphenyl)- 2-oxo-2-((4- (trimethylsilyl)phenyl)amino)ethyl)-N-methyl-1H- pyrrolo[2,3-b]pyridine- 3-carboxamide

485.3 (M − H) 173 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N- methyltetrahydrofuran-2-carboxamide (mixture of four optical isomers)

439.2 (M − H) 174 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N- methyl-2-furamide

435.2 (M − H) 175 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl)amino) ethyl)-N-methyl-1,2- oxazole-5-carboxamide

436.2 (M − H) 176 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl- 2-(pyridin-2-yl)acetamide

460.2 (M − H) 177 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl- 2-(pyridin-3-yl)acetamide

460.3 (M − H) 178 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N- methyltetrahydrothiophene-3-carboxamide 1,1-dioxide (mixture of four optical isomers)

487.2 (M − H) 179 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-5- oxopyrrolidine-3-carboxamide (mixture of four optical isomers)

452.3 (M − H) 180 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-2-oxo-1,2,3,4-tetrahydroquinoline- 6-carboxamide

514.3 (M − H) 181 N-(2-((4-tert-butylphenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-4- hydroxycyclo- hexanecarboxamide (mixtureof four optical isomers)

439.2 (M + H)

TABLE 1-19 Ex. No. IUPAC NAME Structure Salt MS (Found) 182N-(2-((4-tert-butylphenyl) amino)-1-(4-ethylphenyl)-2-oxoethyl)-3-hydroxy-N- methyl-1,2-oxazole-5- carboxamide

434.1 (M − H) 183 N-(2-((4-tert-butylphenyl) amino)-1-(4-ethoxyphenyl)-2-oxoethyl)-3-hydroxy-N- methyl-1,2-oxazole-5- carboxamide

450.0 (M − H) 184 N-(2-((4-tert-butylphenyl) amino)-1-(4-isopropylphenyl)-2-oxoethyl)- 3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

448.1 (M − H) 185 N-(2-((4-tert-butylphenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl) tetrahydrothiophene-3- carboxamide1,1-dioxide (mixture of four optical isomers)

459.2 (M + H) 186 N-(2-((4-tert-butylphenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 5-oxoprolinamide (mixture of four opticalisomers)

424.1 (M + H) 187 N-(2-((4-tert-butylphenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 2-oxoimidazolidine-4- carboxamide (mixtureof four optical isomers)

423.1 (M − H) 188 3-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-1,2-oxazole-5- carboxamide

440.1 (M + H) 189 N-(2-((4-(dimethyl (phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

514.1 (M − H) 190 ethyl ((1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)(methyl) amino)(oxo)acetate

441.1 (M − H) 191 5-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-1,3,4-oxadiazole-2-carboxamide

455.1 (M + H)

TABLE 1-20 Ex. No IUPAC NAME Structure Salt MS (Found) 192N-(2-((4-tert-butylphenyl) amino)-1-(4- methoxyphenyl)-2-oxoethyl)morpholine-4- carboxamide

426.2 (M + H) 193 N-(2-((4-tert-butylphenyl) amino)-1-(4-(methoxyphenyl)-2- oxoethyl)-N-methylmorpholine- 4-carboxamide

440.2 (M + H) 194 N-(1-(2,3-dihydro-1- benzofuran-5-yl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

464.0 (M − H) 195 N-(2-((4-tert-butylphenyl) amino)-1-(4-methoxyphenyl)-2- oxoethyl)-2-oxopiperidine-4- carboxamide (mixture offour optical isomers)

438.2 (M + H) 196 N-(2-((4-(2,2-dimethylpropyl) phenyo)amino)-1-(4-(methoxyphenyl)-2-oxoethyl)- 3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

450.1 (M − H) 197 (3S)-N-((1R)-2-((4-tert- butylphenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 5-oxopyrrolidine-3- carboxamide

424.2 (M + H) 198 (3R)-N-((1R)-2-((4-tert- butylphenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-5- oxopyrrolidine-3- carboxamide

424.2 (M + H) 199 3-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-((trimethylsilyl)methyl) phenyl)amino)ethyl)-N-methyl-1,2-oxazole-5-carboxamide

466.0 (M − H) 200 N-(2-((4-tert-butylphenyl) amino)-1-(4-(methoxyphenyl)-2-oxoethyl)- N-methyl-2-(6-oxo-1,6-dihydropyridin-2-yl)acetamide

462.2 (M + H) 201 N-(4-tert-butylphenyl)-2-(4- methoxyphenyl)-2-(((6-oxo-1,6-dihydropyridin-2-yl) acetyl)amino)acetamide

448.2 (M + H)

TABLE 1-21 Ex. No. IUPAC NAME Structure Salt MS (Found) 202N-(1-(4-methoxyphenyl)- 2-oxo-2-((4- (trimethylsilyl)phenyl)amino)ethyl)-N- methyl-2-oxo-2,3- dihydro-1,3-oxazole-5- carboxamide

452.0 (M − H) 203 2-bromo-N-(2-((4-tert- butylphenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)- N-methyl-1,3-thiazole-5- carboxamide

513.8 (M − H) 204 N-(2-((4-tert- butylphenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)- N-methyl-2-oxo-2,3- dihydro-1,3-thiazole-5-carboxamide

454.1 (M + H) 205 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N- methyl-2-oxo-2,3-dihydro-1,3-oxazole-4- carboxamide

451.9 (M − H) 206 3-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylgermyl)phenyl) amino)ethyl)-N-methyl-1,2-oxazole-5-carboxamide

497.9 (M − H) 207 N-(2-((4-(cyclopropyl (dimethyl)silyl)phenyl)amino)-1-(4- methoxyphenyl)-2-oxoethyl)- 3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

478.0 (M − H) 208 N-(1-(4-ethoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl)amino) ethyl)-5-oxopyrrolidine-3- carboxamide(mixture of four optical isomers)

452.0 (M − H) 209 N-(2-((4-(cyclopropyl (dimethyl)germyl)phenyl)amino)-1- (4-methoxyphenyl)-2-oxoethyl)- 3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

524.0 (M − H) 210 N-(4-tert-butylphenyl)-2- (4-methoxyphenyl)-2-(((6-oxo-1,6-dihydropyridin-3- yl)acetyl)amino)acetamide

448.1 (M + H)

TABLE 1-22 Ex. No. IUPAC NAME Structure Salt MS (Found) 2115-(hydroxymethyl)-N- (1-(4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-1,2-oxazole-3-carboxamide

466.0 (M − H) 212 N-(2-((4-(ethyl(dimethyl) silyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

468.2 (M + H) 213 N-ethyl-3-hydroxy-N-(1- (4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-1,2-oxazole-5- carboxamide

466.0 (M − H) 214 N-(4-tert-butylphenyl)- 2-(1,8-dioxo-2,7-diazaspiro[4.4]non-2-yl)- 2-(4-methoxyphenyl)acetamide (mixture of fouroptical isomers)

450.2 (M + H) 216 N-(2-((4-ethyl(dimethyl)silyl) phenyl)amino)-1-(4-(methoxyphenyl)-2- oxoethyl)-5-oxopyrrolidine-3- carboxamide (mixture offour optical isomers)

454.2 (M + H) 217 N-(2-((4-ethyl(dimethyl) silyl)phenyl)amino)-1-(4-methoxyphenyl)-2- oxoethyl)-2-oxopiperidine-4- carboxamide (mixture offour optical isomers)

468.2 (M + H) 218 N-(2-((2-fluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 5-oxopyrrolidine-3- carboxamide (mixtureof four optical isomers)

458.2 (M + H) 219 N-(2-((2-fluoro-4- (trimethylsilyl)phenyl)amino)-1-(4- methoxyphenyl)-2-oxoethyl)- 3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide

470.0 (M − H) 220 N-(2-((4-tert-butylphenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 4-oxoimidazolidine-1- carboxamide

425.2 (M + H) 221 N-(2-((4-tert-butylphenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 3-methyl-5- oxopyrrolidine-3- carboxamide(mixture of four optical isomers)

438.2 (M + H)

TABLE 1-23 Ex. No. IUPAC NAME Structure Salt MS (Found) 222N-(1-(4-methoxyphenyl)- 2-oxo-2-((4- (trimethylsilyl)phenyl)amino)ethyl)-4- oxoimidazolidine-1- carboxamide

441.2 (M + H) 223 N-(2-((4-(2,2-dimethylpropyl) phenyl)amino)-1-(4-(methoxyphenyl)-2- oxoethyl)-2-oxopiperidine-4- carboxamide (mixture offour optical isomers)

452.2 (M + H) 224 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-2- oxopiperidine-4- carboxamide(mixture of four optical isomers)

454.2 (M + H) 225 3-hydroxy-N-(1-(4- (methoxymethyl) phenyl)-2-oxo-2-(((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-1,2-oxazole-5-carboxamide

466.0 (M − H) 226 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl) tetrahydrofuran-2- carboxamide

427.2 (M + H) 227 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl)amino) ethyl)-2-oxoimidazolidine-4- carboxamide

439.0 (M − H) 228 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl)amino) ethyl)tetrahydrofuran-3- carboxamide

427.2 (M + H) 229 5-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl)amino) ethyl)pyridine-2-carboxamide

450.1 (M + H) 230 6-acetamido-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)nicotinamide

491.3 (M + H) 231 2-((1H-imidazol-4-ylacetyl) amino)-2-(4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide

437.2 (M + H)

TABLE 1-24 Ex. No. UPAC NAME Structure Salt MS (Found) 232 methyl5-((1-(4- methoxyphenyl)- 2-oxo-2-((4- (trimethylsilyl)phenyl)amino)ethyl)(methyl) carbomoyl) pyridine-2-carboxylate

506.2 (M + H) 233 5-((1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)(methyl) carbomoyl)pyridine-2-carboxylic acid

492.2 (M + H) 234 6-(hydroxymethyl)-N-(1- (4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl) phenyl)amino)ethyl)-N- methylnicotinamide

478.2 (M + H) 235 1-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-5- oxopyrrolidine-3- carboxamide(mixture of four optical isomers)

456.1 (M + H) 236 3-hydroxy-N-(1-(4-methoxy- 3-methylphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-1,2-oxazole-5-carboxamide

466.0 (M − H) 237 2-((cyanoacetyl)amino)-2- (4-methoxyphenyl)-N-(4-(trimethylsilyl)phenyl) acetamide

396.2 (M + H) 238 (3Z)-3-amino-3- (hydroxylmino)-N-(1-(4-methoxyphenyl)-2-oxo-2-((4- (trimethylsilyl)phenyl)amino)ethyl)propanamide

429.2 (M + H) 239 2-(4-methoxyphenyl)- 2-(((5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)acetyl) amino)-N-(4- (trimethylsilyl)phenyl) acetamide

453.0 (M − H) 240 1-cyano-N-(1-(4- methoxyphenyl)-2- oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)cyclopropane- carboxamide

422.2 (M + H) 241 1-cyano-N-(1-(4- methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N- methylcyclopropane- carboxamide

434.0 (M − H)

TABLE 1-25 Ex. No IUPAC NAME Structure Salt MS (Found) 242N-(2-((4-tert-butyl-3- chlorophenyl)amino)-1-(4- methoxyphenyl)-2-oxoethyl)-3-hydroxy-N- methyl-1,2- oxazole-5-carboxamide

470.0 (M − H) 243 N-(2-cyanoethyl)-3- hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl) phenyl)amino)ethyl)-1,2-oxazole-5-carboxamide

491.1 (M − H) 244 3-(benzyloxy)-N-(1- (4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)pyrrolidine-1- carboxamide (mixtureof four optical isomers)

532.2 (M + H) 245 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-3- oxopiperazine-1- carboxamide

455.2 (M + H) 246 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-2-oxa-6- azaspiro[3.5]nonane-6-carboxamide

482.2 (M + H) 247 3-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)pyrrolidine-1- carboxamide (mixtureof four optical isomers)

442.2 (M + H) 248 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-2-oxa-6- azaspiro[3.4]octane-6-carboxamide

468.1 (M + H) 249 oxetan-3-yl (1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)carbamate

429.2 (M + H) 250 2-(4-ethoxyphenyl)-2- (((1-methyl-1H-pyrazol-4-yl)acetyl)amino)-N-(4- (trimethylsilyl)phenyl) acetamide

465.1 (M + H) 251 2-(4-ethoxyphenyl)- 2-(((1-methyl-1H-pyrazol-4-yl)acetyl)amino)-N- (4-(trimethylgermyl) phenyl)acetamide

511.2 (M + H)

TABLE 1-26 Ex. No. IUPAC NAME Structure Salt MS (Found) 2522-(2,3-dihydro-1- benzofuran-5-yl)-2- (((1-methyl-1H-pyrazol-4-yl)acetyl)amino)- N-(4-(trimethylsilyl) phenyl)acetamide

463.2 (M + H) 253 2-(4-methoxyphenyl)- 2-((1H-pyrazol-1-yl)acetyl)amino)-N-(4- (trimethylsilyl)phenyl)acetamide

437.2 (M + H) 255 3-cyano-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)azetidine-1- carboxamide

437.2 (M + H) 256 N-(2-((4-tert-butyl-3- cyanophenyl)amino)-1-(4-methoxyphenyl)-2- oxoethyl)-5-oxopyrrolidine-3- carboxamide (mixture offour optical isomers)

449.2 (M + H) 257 2-(4-methoxyphenyl)- 2-((((1-methyl-1H-pyrazol-3-yl)oxy)acetyl)amino)-N-(4- (trimethylsilyl)phenyl) acetamide

467.2 (M + H) 258 3-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)piperidine-1- carboxamide (mixtureof four optical isomers)

456.1 (M + H) 259 2-(hydroxymethyl)-N- (1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)pyrrolidine-1- carboxamide(mixture of four optical isomers)

456.2 (M + H) 260 2-(hydroxymethyl)-N- (1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl) phenyl)amino)ethyl) piperidine-1- carboxamide(mixture of four optical isomers)

470.2 (M + H) 261 (1S,2R)-2-((1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl) phenyl)amino)ethyl) carbamoyl)cyclopentanecarboxylic acid (mixture of four optical isomers)

469.2 (M + H)

TABLE 1-27 Ex. No. IUPAC NAME Structure Salt MS (Found) 2622,3-dihydroxy-N-(1- (4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)propanamide (mixture of four opticalisomers)

417.2 (M + H) 263 3-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)azetidine-1- carboxamide

428.2 (M + H) 264 2-(4-methoxyphenyl)-2- (((4-oxopyridin-1(4H)-yl)acetyl)amino)-N-(4- (trimethylsilyl)phenyl) acetamide

464.2 (M + H) 265 2-(4-methoxyphenyl)- 2-((tetrahydro-2H-pyran-4-ylacetyl)amino)-N-(4- (trimethylsilyl)phenyl) acetamide

455.2 (M + H) 266 2-(4-methoxyphenyl)- 2-((piperidin-1- ylacetyl)amino)-N-(4-(trimethylsilyl) phenyl)acetamide

454.2 (M + H) 267 2-(4-methoxyphenyl)- 2-(((2-oxopyrrolidin-1-yl)acetyl)amino)-N- (4-(trimethylsilyl) phenyl)acetamide

454.2 (M + H) 268 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-2- (2-oxopyrrolidin-1-yl)propanamide (mixture of four optical isomers)

468.2 (M + H) 269 2-(4-methoxyphenyl)- 2-((tetrahydrofuran-2-yl)acetyl)amino)-N- (4-(trimethylsilyl) phenyl)acetamide (mixture offour optical isomers)

441.2 (M + H) 270 2-(4-methoxyphenyl)- 2-((tetrahydrofuran-3-yl)acetyl)amino)-N- (4-(trimethylsilyl)phenyl) acetamide (mixture offour optical isomers)

441.2 (M + H) 271 2-(((2,5-dioxoimidazolidin- 4-yl)acetyl)amino)-2-(4-(methoxyphenyl)-N- (4-(trimethylsilyl) phenyl)acetamide (mixture of fouroptical isomers)

469.2 (M + H)

TABLE 1-28 Ex. NO. IUPAC NAME Structure Salt MS (Found) 2722-(4-methoxyphenyl)- 2-((2-thienyl)acetyl) amino)-N-(4- (trimethylsilyl)phenyl)acetamide

453.2 (M + H) 273 2-(4-methoxyphenyl)- 2-((3-thienylacetyl) amino)-N-(4-(trimethylsilyl) phenyl)acetamide

453.2 (M + H) 274 2-((1H-imidazol-1- ylacetyl)amino)-2-(4-methoxyphenyl)-N- (4-(trimethylsilyl) phenyl)acetamide

437.2 (M + H) 275 2-(4-methoxyphenyl)- 2-((1H-tetrazol-1-ylacetyl)amino)-N- (4-(trimethylsilyl) phenyl)acetamide

437.1 (M − H) 276 2-(4-methoxyphenyl)- 2-((1H-tetrazol-5-ylacetyl)amino)-N- (4-(trimethylsilyl) phenyl)acetamide

439.2 (M + H) 277 2-((1,2-benzoxazol- 3-ylacetyl)amino)-2-(4-methoxyphenyl)-N- (4-(trimethylsilyl) phenyl)acetamide

488.3 (M + H) 278 2-(4-methoxyphenyl)- 2-((pyridin-3-ylacetyl) amino)-N-(4-(trimethylsilyl) phenyl)acetamide

448.2 (M + H) 279 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4- (trimethylsilyl)phenyl)amino)ethyl)- 3-(pyridin-3- yl)propanamide

462.2 (M + H) 280 2-(glycoloylamino)-2- (4-methoxyphenyl)-N-(4-(trimethylsilyl)phenyl) acetamide

387.2 (M + H) 281 3-hydroxy-N-(1-(4- methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)propanamide

401.2 (M + H)

TABLE 1-29 Ex. No. IUPAC NAME Structure Salt MS (Found) 2823-hydroxy-N-(1-(4- methoxyphenyl)- 2-oxo-2-((4- (trimethylsilyl)phenyl)amino)ethyl)butanamide (mixture of four optical isomers)

415.2 (M + H) 283 3-hydroxy-N-(1- (4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-3- methylbutanamide

429.2 (M + H) 284 (3-cyano-N-(1-(4- methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl) propanamide

410.2 (M + H) 285 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4- (trimethylsilyl)phenyl)amino)ethyl) succinamide

428.3 (M + H) 286 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4- (trimethylsilyl)phenyl)amino)ethyl)-3- (methylsulfonyl) propanamide

463.1 (M + H) 287 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N2,N2- dimethylglycinamide

414.2 (M + H) 288 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-pyrazol-1-yl)propanamide (mixture of four optical isomers)

465.1 (M + H) 289 2-((1H-benzimidazol- 1-ylacetyl)amino)-2-(4-methoxyphenyl)-N- (4-(trimethylsilyl) phenyl)acetamide

487.2 (M + H) 290 2-(4-methoxyphenyl)- 2-(((4-methylpiperazin-1-yl)acetyl)amino)-N- (4-(trimethylsilyl)phenyl) acetamide

469.3 (M + H) 291 2-(4-methoxyphenyl)- 2-(((2-oxopyridin-1(2H)-yl)acetyl)amino)-N- (4-(trimethylsilyl) phenyl)acetamide

464.2 (M + H)

TABLE 1-30 Ex. No. IUPAC NAME Structure Salt MS (Found) 2922-(4-methoxyphenyl)- 2-(((2-oxo-1,3-benzoxazol-3(2H)-yl)acetyl)amino)-N-(4- (trimethylsilyl) phenyl)acetamide

504.2 (M + H) 293 2-(((2,4-dioxo-1,3-thiazolidin-3-yl)acetyl)amino)-2-(4- methoxyphenyl)-N- (4-(trimethylsilyl)phenyl)acetamide

486.2 (M + H) 294 2-(((2,5-dioxopyrrolidin- 1-yl)acetyl)amino)-2-(4-methoxyphenyl)-N- (4-(trimethylsilyl) phenyl)acetamide

468.2 (M + H) 295 2-(((2,5-dioxoimidazolidin- 1-yl)acetyl)amino)-2-(4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide

469.2 (M + H) 296 2-(4-methoxyphenyl)- 2-(((2-oxopiperidin-1-yl)acetyl)amino)-N-(4- (trimethylsilyl)phenyl) acetamide

468.2 (M + H) 297 2-(4-methoxyphenyl)- 2-(((2-oxo-1,3-oxazolidin-3-yl)acetyl)amino)-N- (4-(trimethylsilyl)phenyl) acetamide

456.1 (M + H) 298 2-(4-methoxyphenyl)-2- (((2-oxoimidazolidin-1-yl)acetyl)amino)-N-(4- (trimethylsilyl)phenyl) acetamide

455.2 (M + H) 299 2-(4-methoxyphenyl)- 2-(((3-methyl-2,5-dioxoimidazolidin-1-yl) acetyl)amino)-N-(4- (trimethylsilyl)phenyl)acetamide

483.2 (M + H) 300 2-(4-methoxyphenyl)-2- ((morpholin-4-ylacetyl)amino)-N-(4-(trimethylsilyl) phenyl)acetamide

456.1 (M + H) 301 2-(((2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)acetyl)amino)-2- (4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl)acetamide

481.2 (M + H)

TABLE 1-31 Ex. No. IUPAC NAME Structure Salt MS (Found) 3022-(((2,4-dioxo-1,3- oxazolidin-3-yl) acetyl)amino)-2-(4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide

470.1 (M + H) 303 2-(((3-(difluoromethyl)- 5-methyl-1H-pyrazol-1-yl)acetyl)amino)-2-(4- methoxyphenyl)-N-(4- (trimethylsilyl)phenyl)acetamide

501.2 (M + H) 304 2-(4-methoxyphenyl)-2- (((4-oxopiperidin-1-yl)acetyl)amino)-N-(4- (trimethylsilyl)phenyl) acetamide

468.3 (M + H) 305 2-(((3,5-dioxomorpholin- 4-yl)acetyl)amino)-2-(4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide

484.2 (M + H) 306 2-(((2-ethyl-1H-imidazol- 1-yl)acetyl)amino)-2-(4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide

465.1 (M + H) 307 2-(4-methoxyphenyl)- 2-(((3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl) amino)-N-(4- (trimethylsilyl)phenyl) acetamide

505.2 (M + H) 308 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl)amino)ethyl)-2- methyl-2-(1H- pyrazol-1-yl)propanamide

465.1 (M + H) 309 2-(((2,6-dioxo-3,6- dihydropyrimidin-1(2H)-yl)acetyl)amino)-2- (4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl)acetamide

481.2 (M + H) 310 2-(((3-hydroxypyrrolidin- 1-yl)acetyl)amino)-2-(4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide (mixture of fouroptical isomers)

456.1 (M + H) 311 2-(4-methoxyphenyl)-2- (((4-oxoimidazolidin-1-yl)acetyl)amino)-N- (4-(trimethylsilyl) phenyl)acetamide

455.2 (M + H)

TABLE 1-32 Ex. No. IUPAC NAME Structure Salt MS (Found) 312 N-(1-(3,4-dimethoxyphenyl)-2-oxo- 2-((4-(trimethylsilyl) phenyl)amino)ethyl)-3-hydroxy-N-methyl- 1,2-oxazole-5- carboxamide

482.0 (M − H) 313 3-hydroxy-N-(1-(4- (hydroxymethyl)phenyl)-2-oxo-2-((4-(trimethylsilyl) phenyl)amino)ethyl)- N-methyl-1,2-oxazole-5-carboxamide

452.0 (M − H) 314 N-(3-cyano-4- (trimethylsilyl)phenyl)-2-(4-methoxyphenyl)-2- (((4-oxopyridin-1(4H)- yl)acetyl)amino) acetamide

489.2 (M + H) 315 2-(((3-hydroxypiperidin- 1-yl)acetyl)amino)-2-(4-methoxyphenyl)-N- (4-(trimethylsilyl) phenyl)acetamide (mixture of fouroptical isomers)

470.3 (M + H) 316 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-3- oxocyclopentane- carboxamide(mixture of four optical isomers)

439.2 (M + H) 317 (1R,2S)-2-(hydroxymethyl)- N-(1-(4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl) phenyl)amino)ethyl) cyclopentanecarboxamide(mixture of four optical isomers)

453.1 (M − H) 318 3-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl) cyclopentanecarboxamide(mixture of four optical isomers)

441.2 (M + H) 319 3-(hydroxymethyl)-N- (1-(4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl) phenyl)amino)ethyl) piperidine-1-carboxamide (mixture of four optical isomers)

470.3 (M + H) 320 2-(((3-hydroxyazetidin- 1-yl)acetyl)amino)-2-(4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide

442.2 (M + H) 321 2-(3-hydroxypyrrolidin- 1-yl)-N-(1-(4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl) phenyl)amino)ethyl)-2- methylpropanamide(mixture of four optical isomers)

484.3 (M + H)

TABLE 1-33 Ex. No. IUPAC NAME Structure Salt MS (Found) 3222-(((3-(benzyloxy)- 1-ethyl-1H-pyrazol-4- yl)acetyl)amino)-2-(4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide

571.3 (M + H) 323 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-3- oxocyclohexanecarboxamide(mixture of four optical isomers)

453.2 (M + H) 324 2-(((3-cyanoazetidin-1-yl) acetyl)amino)-2-(4-(methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide

451.2 (M + H) 325 N-(1-(4-(ethoxymethyl) phenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-3- hydroxy-N-methyl-1,2-oxazole-5-carboxamide

480.1 (M − H) 326 N-(1-(4-((2,2-difluoroethoxy) methyl)phenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-3-hydroxy-N-methyl-1,2-oxazole-5- carboxamide

516.0 (M − H) 327 3-hydroxy-N-(1-(4-((2- methoxyethoxy)methyl)phenyl)-2-oxo-2-((4- (trimethylsilyl)phenyl) amino)ethyl)-N-methyl-1,2-oxazole-5- carboxamide

510.1 (M − H) 328 3-hydroxy-N-(1-(4-((3- methoxypropoxy)methyl)phenyl)-2-oxo-2-((4- (trimethylsilyl)phenyl)amino)ethyl)-N-methyl-1,2- oxazole-5-carboxamide

526.3 (M + H) 329 2-(((1-hydroxycyclopentyl) acetyl)amino)-2-(4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide

455.2 (M + H) 330 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl)amino)ethyl)-N,5- dimethyl-1,3,4- oxadiazole-2-carboxamide

453.2 (M + H) 331 2-(4-(methoxymethyl) phenyl)-2-(((4-oxopyridin-1(4H)-yl)acetyl)amino)-N- (4-(trimethylsilyl)phenyl) acetamide

478.2 (M + H)

TABLE 1-34 Ex. No. IUPAC NAME Structure Salt MS (Found) 3323-hydroxy-N-(1-(4-(2- methoxyethoxy)phenyl)-2-oxo-2-((4-(trimethylsilyl) phenyl)amino)ethyl)- N-methyl-1,2-oxazole-5-carboxamide

496.1 (M − H) 333 3-hydroxy-N-(1-(4-(3- methoxypropoxy)phenyl)-2-oxo-2-((4-(trimethylsilyl) phenyl)amino)ethyl)-N- methyl-1,2-oxazole-5-carboxamide

510.1 (M − H) 334 N-(1-(4-(methoxymethyl)phenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-5-oxopyrrolidine- 3-carboxamide(mixture of four optical isomers)

452.0 (M − H) 335 3-hydroxy-N-(1-(4- methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl) phenyl)amino)ethyl) cyclohexanecarboxamide(mixture of four optical isomers)

455.2 (M + H) 336 2-(((1-ethyl-5-hydroxy- 1H-pyrazol-4-yl)acetyl)amino)-2-(4-methoxyphenyl)- N-(4-(trimethylsilyl) phenyl)acetamide

481.2 (M + H) 337 N-((1S)-2-((2,5-difluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2- oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5- carboxamide

488.0 (M − H) 338 N-(1-(4-methoxyphenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N- methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazole- 3-carboxamide

453.1 (M − H) 339 2-(((3-cyanopyrrolidin- 1-yl)acetyl)amino)-2-(4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide (mixture of fouroptical isomers)

465.1 (M + H) 340 N-(2-((3-cyano-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)- 2-oxoethyl)-3-hydroxy- N-methyl-1,2-oxazole-5-carboxamide

477.1 (M − H) 341 2-(((5-hydroxy-1-methyl- 1H-pyrazol-3-yl)acetyl)amino)-2- (4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl)acetamide

467.2 (M + H)

TABLE 1-35 Ex. No. IUPAC NAME Structure Salt MS (Found) 3422-(((1-ethyl-3-hydroxy- 1H-pyrazol-4-yl)acetyl)amino)-2-(4-methoxyphenyl)- N-(4-(trimethylsilyl) phenyl)acetamide

481.2 (M + H) 343 2-(((1-cyanocyclopentyl) acetyl)amino)-2-(4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl)acetamide

464.2 (M + H) 344 2-(4-(methoxymethyl)phenyl)- 2-(((5-methyl-1,3,4-oxadiazol-2-yl)acetyl) amino)-N-(4- (trimethylsilyl)phenyl) acetamide

467.2 (M + H) 345 N-(2-((3-chloro-4-(1- cyanocyclopentyl)phenyl)amino)-1-(4- methoxyphenyl)-2- oxoethyl)-5-oxopyrrolidine- 3-carboxamide(mixture of four optical isomers)

495.2 (M + H) 346 2-(4-methoxyphenyl)-2- (((5-oxopyrrolidin-3-yl)acetyl)amino)-N-(4- (trimethylsilyl)phenyl) acetamide (mixture offour optical isomers)

454.2 (M + H) 347 2-(((1-benzyl-3-hydroxy- 1H-pyrazol-4-yl)acetyl)amino)-2-(4- methoxyphenyl)-N-(4- (trimethylsilyl)phenyl)acetamide

543.2 (M + H) 348 2-(3-hydroxyazetidin-1-yl)- N-(1-(4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl) phenyl)amino)ethyl)-2- methylpropanamide

470.2 (M + H) 349 2-(((3-hydroxy-1H-pyrazol- 4-yl)acetyl)amino)-2-(4-(methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide

453.2 (M + H) 350 2-(4-methoxyphenyl)-2- (((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)amino)-N-(4- (trimethylsilyl)phenyl) acetamide

453.2 (M + H) 351 3-hydroxy-N-(1-(4- (methoxymethyl)phenyl)- 2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)pyrrolidine-1- carboxamide(mixture of four optical isomers)

456.2 (M + H)

TABLE 1-36 Ex. No. IUPAC NAME Structure Salt MS (Found) 352N-(1-(4-methoxyphenyl)- 2-oxo-2-((4- (trimethylsilyl)phenyl)amino)ethyl)-2-(1-methyl-1H- pyrazol-4-yl)propanamide

465.2 (M + H) 353 2-(((3-hydroxy-1-methyl- 1H-pyrazol-5-yl)acetyl)amino)-2-(4- methoxyphenyl)-N-(4- (trimethylsilyl)phenyl)acetamide

467.2 (M + H) 354 N-(1-(4-(1-hydroxyethyl) phenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-5-oxopyrrolidine-3- carboxamide(mixture of eight optical isomers)

452.0 (M − H) 355 2-(((2-hydroxy-2- methylpropyl)carbamoyl) amino)-2-(4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide

444.2 (M + H) 356 2-(((3-(benzyloxy)-1,2- oxazol-5-yl)acetyl)amino)-2-(4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide

544.3 (M + H) 357 2-(((3-hydroxy-1,2-oxazol- 5-yl)acetyl)amino)-2-(4-methoxyphenyl)-N-(4- (trimethylsilyl)phenyl) acetamide

454.2 (M + H) 358 ((3S)-3-hydroxy-N-((1R)- 1-(4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl) phenyl)amino)ethyl) pyrrolidine-1- carboxamide

442.2 (M + H) 359 (3R)-3-hydroxy-N-((1R)- 1-(4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)pyrrolidine-1- carboxamide

442.2 (M + H) 360 N-(1-(4-((2,2-difluoroethoxy) methyl)phenyl)-2-((3-fluoro-4-(trimethylsilyl) phenyl)amino)-2-oxoethyl)-3-hydroxy-N-methyl-1,2- oxazole-5-carboxamide

534.2 (M − H) 361 N-(1-(4-((2,2-difluoroethoxy) methyl)phenyl)-2-((2-fluoro-4-(trimethylsilyl) phenyl)amino)-2-oxoethyl)-3-hydroxy-N-methyl-1,2- oxazole-5-carboxamide

534.2 (M − H)

TABLE 1-37 Ex. No. IUPAC NAME Structure Salt MS (Found) 3622-(4-methoxyphenyl)-2- (((6-oxopyrimidin-1(6H)- yl)acetyl)amino)-N-(4-(trimethylsilyl)phenyl) acetamide

465.2 (M + H) 363 2-(4-(methoxymethyl)phenyl)- 2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)- N-(4-(trimethylsilyl) phenyl)acetamide

479.2 (M + H) 364 3-hydroxy-N-(1-(4-(1- methoxyethyl)phenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-1,2-oxazole-5-carboxamide (mixture of four optical isomers)

480.1 (M − H) 365 tert-butyl (2-hydroxy-4- ((1-(4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl)phenyl) amino)ethyl)amino)-4- oxobutyl)carbamate(mixture of four optical isomers)

528.2 (M − H) 366 2-(((3-(benzyloxy)-1,2- oxazol-5-yl)acetyl)amino)-N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-(4- (methoxymethyl)phenyl)acetamide

592.2 (M − H) 367 N-(2-fluoro-4-(trimethylsilyl) phenyl)-2-(4-(methoxymethyl)phenyl)-2- (((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

497.2 (M + H) 368 N-(2-fluoro-4-(trimethylsilyl) phenyl)-2-(4-(methoxymethyl)phenyl)-2- (((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)amino)acetamide

485.2 (M + H) 369 3-hydroxy-N-(1-(4-(1- hydroxyethyl)phenyl)-2-oxo-2-(4-(trimethylsilyl)phenyl) amino)ethyl)-N-methyl-1,2-oxazole-5-carboxamide (mixture of four optical isomers)

466.1 (M − H) 370 N-(2-((4-tert-butyl-3- cyanophenyl)amino)-1-(4-(methoxymethyl)phenyl)- 2-oxoethyl)-3- hydroxypyrrolidine-1- carboxamide(mixture of four optical isomers)

465.2 (M + H) 371 N-(2-((4-tert-butyl-3- cyanophenyl)amino)-1-(4-(methoxymethyl)phenyl)- 2-oxoethyl)-3- hydroxyazetidine-1- carboxamide

451.2 (M + H)

TABLE 1-38 Ex. No. IUPAC NAME Structure Salt MS (Found) 372N-(2-((4-tert-butyl-3- cyanophenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine- 3-carboxamide (mixture of four opticalisomers)

461.1 (M − H) 373 N-(2-((3-cyano-4- (trimethylsilyl)phenyl) amino)-1-(4-((methoxymethyl)phenyl)- 2-oxoethyl)-3-hydroxy-N- methyl-1,2-oxazole-5-carboxamide

491.2 (M − H) 374 N-(2-((3-cyano-4- (trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 3-hydroxyazetidine-1- carboxamide

453.1 (M + H) 375 N-(2-((3-cyano-4- (trimethylsilyl)phenyl) amino)-1-(4-(methoxymethyl)phenyl)- 2-oxoethyl)-3- hydroxyazetidine-1- carboxamide

465.1 (M − H) 376 N-(2-((4-tert-butyl-3- cyanophenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)- 3-hydroxypyrrolidine-1- carboxamide (mixtureof four optical isomers)

451.2 (M + H) 377 N-(2-((2,5-difluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)- 2-oxoethyl)-3- hydroxyazetidine-1-carboxamide

464.2 (M + H) 378 N-(2-((3-cyano-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)- 2-oxoethyl)-3- hydroxypyrrolidine-1-carboxamide (mixture of four optical isomers)

467.2 (M + H) 379 3-hydroxy-N-((1R)-1- (4-methoxyphenyl)-2-oxo-2-((4-(trimethylsilyl) phenyl)amino)ethyl) azetidine-1- carboxamide

428.2 (M + H) 380 (3S)-N-(1S)-2-((3-fluoro-4- (trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)- 2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

470.1 (M − H) 381 (3S)-N-((1S)-2-((3-fluoro-4- (trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2- oxoethyl)-5-oxopyrrolidine- 3-carboxarnide

458.2 (M + H)

TABLE 1-39 Ex. No. IUPAC NAME Structure Salt MS (Found) 3824-(((1R)-2-((3-fluoro-4- (trimethylsilyl)phenyl) amino)-1-(4-(methoxymethyl)phenyl)- 2-oxoethyl)amino)-4- oxobutanoic acid

459.1 (M − H) 384 N-((1R)-2-((3-fluoro-4- (trimethylsilyl)phenyl)amino)-1- (4-(methoxymethyl)phenyl)- 2-oxoethyl)-3-hydroxy-1,2-oxazole-5-carboxamide

472.2 (M + H) 385 N-((1R)-2-((4-tert-butyl- 3-flourophenyl)amino)-1-(4-(methoxymethyl) phenyl)-2-oxoethyl)-3- hydroxy-1,2-oxazole-5-carboxamide

456.1 (M + H) 386 4-(((1R)-2-((3,5-difluoro-4- (trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)- 2-oxoethyl)amino)-3,3-dimethyl-4-oxobutanoic acid

507.1 (M + H) 387 N-(2-((4-tert-butyl-3- chlorophenyl)amino)-1-(4-(methoxymethyl)phenyl)- 2-oxoethyl)-3-hydroxy-1,2- oxazole-5-carboxamide

472.2 (M + H) 388 N-(4-tert-butyl-3- chlorophenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide

497.2 (M + H) 389 N-(3,5-difluoro-4- (trimethylsilyl)phenyl)-2-(4-(methoxymethyl) phenyl)-2-(2-oxopyrrolidin- 1-yl)acetamide

447.1 (M + H) 390 6-(((1R)-2-((3,5- difluoro-4- (trimethylsilyl)phenyl)amino)-1-(4- (methoxymethyl)phenyl)- 2-oxoethyl)amino)-6- oxohexanoicacid

507.2 (M + H) 391 (3S)-N-(2-((4-tert-butyl- 3-fluorophenyl)amino)-1-(2,3-dihydro-1- benzofuran-5-yl)-2- oxoethyl)-5- oxopyrrolidine-3-carboxamide (mixture of two diastereomers)

452.2 (M − H)

TABLE 1-40 Ex. No. UPAC NAME Structure Salt MS (Found) 392N-(2-((4-tert-butyl-3- fluorophenyl)amino)-1-(2,3- dihydro-1-benzofuran-5-yl)-2-oxoethyl)-3-hydroxy- 1,2-oxazole-5-carboxamide

454.1 (M + H) 393 N-(2-((3-fluoro-4- (trimethylsilyl)phenyl)amino)-1-(1- methyl-1H-indazol-5-yl)- 2-oxoethyl)-3-hydroxy-1,2-oxazole-5-carboxamide

480.1 (M − H) 394 (3S)-N-(2-((4-tert-butyl- 3-fluorophenyl)amino)-1-(4-(2-hydroxypropan-2-yl) phenyl)-2-oxoethyl)-5- oxopyrrolidine-3-carboxamide (mixture of two diastereomers)

468.2 (M − H) 395 (3R)-N-(2-((4-tert-butyl- 3-fluorophenyl)amino)-1-(4-(2-hydroxypropan-2-yl) phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide (mixture of two diastereomers)

468.2 (M − H) 396 ((3S)-N-(2-((4-(2,2- dimethylpropyl)-3-fluorophenyl)amino)- 1-(4-(2-hydroxypropan-2- yl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3- carboxamnide (mixture of two diastereomers)

482.0 (M − H) 397 5-((2-((4-(2,2-dimethylpropyl)- 3-fluorophenyl)amino)-1-(4-(methoxymethyl) phenyl)-2-oxoethyl)amino)- 5-oxopentanoic acid

473.2 (M + H) 398 (3S)-N-(2-((4-tert-butyl- 3-fluorophenyl)amino)-1-(1-(methyl-1H-indol-5-yl)- 2-oxoethyl)-5-oxopyrrolidine-3- carboxamide(mixture of two diastereomers)

463.0 (M − H) 399 (3R)-N-(2-((4-tert-butyl- 3-fluorophenyl)amino)-1-(1-methyl-1H-indol-5-yl)- 2-oxoethyl)-5-oxopyrrolidine-3- carboxamide(mixture of two diastereomers)

465.1 (M + H) 400 (3S)-N-(2-((4-tert-butyl- 3-fluorophenyl)amino)-1-(1-(4-tert-butyl-3-fluorophenyl) amino)-1-(1-methyl-2,3-dihydro-1H-indol-5-yl)- 2-oxoethyl)-5- oxopyrrolidine-3- carboxamide(mixture of two diastereomers)

465.1 (M − H) 401 (3R)-N-(2-((4-tert-butyl- 3-fluorophenyl)amino)-1-(1-(methyl-2,3-dihydro-1H- indol-5-yl)-2-oxoethyl)-5- oxopyrrolidine-3-carboxamide (mixture of two diastereomers)

465.1 (M − H)

TABLE 1-41 Ex. No. IUPAC NAME Structure Salt MS (Found) 402(3S)-N-((1R)-2-((4-tert- butyl-3-fluorophenyl)amino)-1-(4-(2-hydroxypropan- 2-yl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

468.2 (M − H) 406 (3R)-N-(2-((4-tert-butyl-3- fluorophenyl)amino)-1-(4-(2-hydroxypropan-2-yl) phenyl)-2-oxoethyl)-5- oxopyrrolidine-3-carboxamide

468.2 (M − H) 407 N-(2-((4-tert-butyl-3- fluorophenyl)amino)-1-(4-(2-hydroxypropan-2-yl) phenyl)-2-oxoethyl) tetrahydrothiophene-3-carboxamide 1,1-dioxide (mixture of four optical isomers)

505.2 (M + H) 409 (3R)-N-((1S)-2-((4-tert- butyl-3,5-(difluorophenyl)amino)-1-(4-(methoxymethyl) phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide

472.1 (M − H) 410 (3S)-N-(2-((4-(2,2- dimethylpropyl)-3-fluorophenyl)amino)-1- (4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine- 3-carboxamide

470.2 (M + H) 411 (2R)-N-(4-tert-butyl-3- fluorophenyl)-2-(4-(methoxymethyl)phenyl)- 2-(((2-oxoimidazolidin-1-yl)acetyl)amino)acetamide

471.2 (M + H) 412 (2R)-N-(4-tert-butyl-3- fluorophenyl)-2-(4-(methoxymethyl)phenyl)- 2-((pyridazin-3- yl)carbamoyl)amino) acetamide

466.1 (M + H) 413 N-(4-tert-butyl-3,5- difluorophenyl)-2-(((3-hydroxy-(1,2-oxazol-5- yl)acetyl)amino)-2-(1- methyl-1H-indazol-5-yl)acetamide

498.1 (M + H) 414 N-(4-tert-butyl-3,5- difluorophenyl)-2-(((3-hydroxy-1,2-oxazol-5- yl)acetyl)amino)-2-(2- methyl-2H-indazol-5-yl)acetamide

498.1 (M + H) 415 N-(3-fluoro-4-(trimethylsilyl) phenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)- 2-(1-methyl-1H-indazol- 5-yl)acetamide

496.1 (M + H)

TABLE 1-42 Ex. No. IUPAC NAME Structure Salt MS (Found) 416N-(2-((4-(1-(cyclopropyl- amino)-2-methyl-1- oxopropan-2-yl)-3-fluorophenyl)amino)- 1-(4-(methoxymethyl) phenyl)-2-oxoethyl)-3,3,3-trifluoropropanamide

524.2 (M + H) 417 3,3,3-triflouro-N-(2-((3- fluoro-4-(2-methyl-1-oxo-1-(pyrrolidin-1-yl)propan- 2-yl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)- 2-oxoethyl)propanamide

538.2 (M + H) 418 (2S)-N-(4-tert-butyl-3,5- difluorophenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl) acetyl)amino)-2-(1-methyl-1H-indazol-5-yl)acetamide

498.1 (M + H) 419 (2R)-N-(4-tert-butyl-3,5- difluorophenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl) acetyl)amino)-2-(1-methyl-1H-indazol-5-yl)acetamide

498.1 (M + H)

The compounds of Examples 421 to 426 were synthesized in the same manneras in Examples 1 to 126, 128 to 154, 156 to 214, 216 to 253, 255 to 382,384 to 402, 406, 407 and 409 to 419.

The compounds described in Examples 421 to 426 are as follows (Table1-43).

TABLE 1-43 Ex. No. IUPAC NAME Structure Salt MS (Found) 421N-(2-((3-fluoro-4-(1- methoxy-2-methylpropan-2- yl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2- oxoethyl)-3-hydroxy-1,2- oxazole-5-carboxamide

486.1 (M + H) 422 N-(3-fluoro-4-(1-methoxy- 2-methylpropan-2-yl)phenyl)-2-(((3-hydroxy- 1,2-oxazol-5- yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl) acetamide

500.2 (M + H) 423 5-((2-((3,5-difluoro-4- (trimethylsilyl)phenyl)amino)-2-oxo-1-(tetrahydro- 2H-pyran-4-yl)ethyl) (methyl)amino)-5-oxopentanoic acid

469.1 (M − H) 424 N-(2-((3,5-difluoro-4- (trimethylsilyl)phenyl)amino)-2-oxo- 1-(tetrahydro-2H- pyran-4-yl)ethyl)- 2-(3-hydroxy-1,2-oxazol-5-yl)-N- methylacetamide

479.9 (M − H) 425 N-((1R)-2-((3,5-difluoro-4- (trimethylsilyl)phenyl)amino)-2-oxo-1-(tetrahydro- 2H-pyran-4-yl)ethyl)-3-hydroxy-N-methyl-1,2- oxazole-5-carboxamide

466.0 (M − H) 426 N-((1R)-2-((4-tert-butyl- 3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)- 2-oxoethyl)-3-hydroxy-N- methyl-1,2-oxazole-5-carboxamide

466.0 (M − H)

Example 4275-((2Z)-2-((1-(difluoroboryl)-3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrol-5-yl)-N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)pentanamide

To a solution of(R)-2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide(9.07 mg, 0.02 mmol) in DMF (0.5 ml) was added1-((5-((2Z)-2-((1-(difluoroboryl)-3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrol-5-yl)pentanoyl)oxy)pyrrolidine-2,5-dione(BODIPY (trade name) FL-C5 succinimidyl ester) (5.0 mg, 0.01 mmol) atroom temperature, and the mixture was stirred at room temperature for 3hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,and dried over magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (solvent; ethyl acetate/hexane), and then preparativeHPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) togive the title compound (3.8 mg, 5.58 μmol, 46.6%) as an orange solid.

¹H NMR (300 MHz, CDCl₃): δ0.31 (9H, t, J=1.3 Hz), 1.71-1.87 (4H, m),2.25 (3H, s), 2.32-2.42 (2H, m), 2.53 (3H, s), 2.91-3.03 (2H, m), 3.35(3H, s), 4.40 (2H, s), 5.71 (1H, d, J=7.2 Hz), 6.09 (1H, s), 6.23 (1H,d, J=4.2 Hz), 6.80-6.90 (2H, m), 6.90-6.99 (2H, m), 7.06 (1H, s),7.23-7.31 (2H, m), 7.33-7.42 (2H, m), 8.63 (1H, s).

MS(API): Calculated 680.6, Found 679.3 (M−H).

The compound described in Example 427 is as follows (Table 1-44).

TABLE 1-44 MS Ex. No. IUPAC NAME Structure Salt (Found) 4275-((2Z)-2-((1-(difluoroboryl)- 3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrol-5- yl)-N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl) phenyl)amino)-1-(4- (methoxymethyl)phenyl)-2-oxoethyl)pentanamide

679.3 (M − H)

Experimental Example 1

RORγt Binding Test

The binding activity of the test compound to RORγt was measured by atime resolved fluorescence resonance energy transfer method (TR-FRET)utilizing histidine-tagged RORγt, fluorescent-labeled cholesterol(BODIPY-cholesterol, AVIVA), and terbium-labeled anti-histidine tagantibody (Invitrogen). First, a test compound diluted with an assaybuffer (20 mM Tris-HCl (pH 7.5), 100 mM NaCl, 1 mM DTT, 0.1% BSA) wasadded to a 384 well plate by 3 μL. Then, RORγt diluted with an assaybuffer to 240 nM was added by 3 μL, after which fluorescent-labeledcholesterol diluted with the assay buffer to 12 μM was added by 3 μL,and the mixture was stood at room temperature for 20 min. Thereafter, aterbium-labeled anti-histidine tag antibody diluted with the assaybuffer to 8 nM was added by 3 μL. The mixture was stood at roomtemperature for 20 min, and fluorescence intensity (excitationwavelength 320 nm, fluorescence wavelength 520 nm, delay time 100microseconds) was measured by Envision (PerkinElmer).

The results (binding inhibitory rate of fluorescent-labeled cholesterolto RORγt at test compound 1 μM) measured by the above-mentioned methodare shown in Tables 2-1 to 2-5.

Experimental Example 2

Cofactor Recruitment Test

Cofactor recruitment test was performed by Alpha Screen (HistidineDetection Kit, PerkinElmer) method. First, a test compound was dilutedwith an assay buffer (50 mM Tris-HCl (pH 7.5), 50 mM KCl, 1 mM DTT, 0.1%BSA) and added to a 384 well plate by 5 μL. Then, RORγt diluted with anassay buffer to 125 nM was added by 10 μL each, after which solutions of25 nM biotinylated SRC-1 peptide (biotin-CLTARHKILHRLLQEGSPSD), 12.5μg/mL acceptor beads and 12.5 μg/mL donor beads prepared with the assaybuffer were added by 10 μL each. The mixture was stood in a dark placefor 1 hr, and the signal value was measured by Envision (PerkinElmer).

The results (signal value inhibitory rate at test compound 1 μM)measured by the above-mentioned method are shown in Tables 2-1 to 2-5.

Experimental Example 3

Jurkat Reporter Test

The Jurkat cells used for the reporter test were cultured in a culturemedium (RPMI (Invitrogen), 10% FCS (AusGeneX), 100 U/mL penicillin, 100μg/mL streptomycin). On the day of the test, 4×10⁷ cells were recoveredby a centrifugal operation (1000 rpm, 5 min.) and suspended in PBS(phosphate buffered saline) (Invitrogen). Thereafter, the cells wererecovered again by a centrifugal operation, and suspended in 2 mL of Rbuffer (NEON transfection kit, Invitrogen). Then, a reporter vector 53μg wherein a human IL-17 ROR response element was inserted into theupstream of luciferase of pGL 4.28 (Promega), and a vector (27 μg)wherein RORγt sequence was inserted into the downstream of CMV promoterwere added to the cell suspension. Gene transfer was performed byElectroporation apparatus (NEON, Invitrogen) under the conditions ofpulse voltage 1350 V, interval 10 milliseconds, number of times 3. Thecells after gene transfer were suspended in 40 mL of a reaction medium(RPMI, 10% Lipid reduced FCS (HyClone), 10 mM HEPES (pH 7.5), 100 U/mLpenicillin, 100 μg/mL streptomycin, 5 μM lovastatin), and plated in a 96well plate by 90 μL. A test compound diluted with the reaction mediumwas added by 10 μL, and the cells were cultured overnight in anincubator. Bright-Glo (Promega) was added by 100 μL, and the mixture wasstirred at room temperature for 10 min, and the luminescence level wasmeasured by Envision (PerkinElmer).

The results (luminescence level inhibitory rate at test compound 3 μM)measured by the above-mentioned method are shown in Tables 2-1 to 2-5.

TABLE 2-1 Experimental Example 1 Experimental Experimental bindinginhibitory Example 2 Example 3 rate (%) of signal value luminescencelevel fluorescent-labeled inhibitory rate inhibitory rate cholesterol toRORγt (%) at test (%) at test Ex. No. at test compound 1 μM compound 1μM compound 3 μM 1 100 72.7 97.3 2 102 78.0 98.1 3 100 72.3 98.4 4 10078.8 97.0 5 100 84.8 98.0 6 102 99.4 101 7 102 56.9 97.0 8 102 49.1 93.49 100 29.7 97.6 10 102 2.04 95.3 11 102 32.0 97.5 12 101 89.0 116 13 10151.1 92.6 14 103 85.5 119 15 109 91.6 99.4 16 102 81.9 93.2 17 102 94.698.8 18 101 60.3 90.9 19 101 50.7 84.7 20 101 73.0 91.8 21 101 93.1 98.322 101 90.6 97.2 23 102 96.5 101 24 102 95.3 100 25 102 95.7 100

TABLE 2-2 Experimental Example 1 Experimental Experimental bindinginhibitory Example 2 Example 3 rate (%) of signal value luminescencelevel fluorescent-labeled inhibitory rate inhibitory rate cholesterol toRORγt (%) at test (%) at test Ex. No. at test compound 1 μM compound 1μM compound 3 μM 26 103 99.5 97.6 27 103 92.5 96.0 28 100 88.0 98.0 29101 92.3 99.2 30 98.5 95.1 99.8 31 99.5 98.3 99.5 32 95.2 95.6 99.1 33101 97.7 98.4 34 101 98.9 99.2 35 103 96.6 101 36 96.2 98.2 99.8 37 10193.6 98.5 38 102 99.7 100 39 103 99.6 100 40 101 98.7 100 41 101 94.4100 42 102 88.5 99.1 43 102 96.1 100 44 102 95.7 102 45 102 94.1 101 4699.5 87.2 101 47 100 92.4 100 48 103 73.0 95.7 49 101 96.9 98.4 50 10291.5 98.0

TABLE 2-3 Experimental Example 1 Experimental Experimental bindinginhibitory Example 2 Example 3 rate (%) of signal value luminescencelevel fluorescent-labeled inhibitory rate inhibitory rate cholesterol toRORγt (%) at test (%) at test Ex. No. at test compound 1 μM compound 1μM compound 3 μM 51 102 97.3 98.0 52 102 98.7 100 53 102 97.8 98.4 54102 95.6 99.0 55 102 95.8 98.6 56 102 97.7 100 57 103 97.3 98.9 58 10297.1 98.4 59 102 96.0 99.2 60 102 96.6 99.7 61 102 97.0 100 62 99.9 96.397.8 63 103 95.1 99.7 64 102 90.1 98.7 65 102 94.3 98.5 66 103 94.6 98.567 103 96.0 98.5 68 101 96.2 98.7 69 103 96.8 98.4 70 101 82.8 96.5 71101 89.9 99.0 72 102 96.7 99.2 73 103 96.7 97.9 74 101 97.6 99.4 75 10295.8 99.7

TABLE 2-4 Experimental Example 1 Experimental Experimental bindinginhibitory Example 2 Example 3 rate (%) of signal value luminescencelevel fluorescent-labeled inhibitory rate inhibitory rate cholesterol toRORγt (%) at test (%) at test Ex. No. at test compound 1 μM compound 1μM compound 3 μM 76 103 98.5 99.3 77 103 97.3 99.7 78 102 93.2 96.0 79103 93.0 98.4 80 102 93.8 100 81 103 94.9 98.3 82 103 96.8 97.0 83 10086.5 63.2 84 101 94.4 100 85 103 90.1 99.0 86 102 95.2 99.1 87 102 83.998.2 88 103 90.7 98.1 89 103 95.5 101 90 102 96.0 101 91 102 94.6 98.092 102 92.8 98.8 93 102 92.3 99.1 94 102 91.5 101 95 99.3 93.8 99.8 9698.6 91.2 99.5 97 102 93.6 98.3 98 102 95.8 99.2 99 102 94.3 99.9 10099.6 86.3 99.4

TABLE 2-5 Experimental Example 1 Experimental Experimental bindinginhibitory Example 2 Example 3 rate (%) of signal value luminescencelevel fluorescent-labeled inhibitory rate inhibitory rate cholesterol toRORγt (%) at test (%) at test Ex. No. at test compound 1 μM compound 1μM compound 3 μM 101 101 87.6 99.5 102 100 83.8 97.8 103 102 96.2 100104 101 74.9 96.1 105 101 85.5 100 106 103 88 99.8 107 103 95.7 100 108100 95.3 99.7 109 100 87.6 100 110 99.6 71.1 95.4 111 100 53 97.4 112103 83.2 100 113 102 83.9 99.7 114 101 90.1 102 115 102 71.6 97.3 116103 76.6 99.8 117 103 78.4 98.5 289 99.6 87.2 100 419 103 87 101

Experimental Example 4

Effect on IL-23-Induced IL-17A Gene Expression in Mice

A mouse IL-23 solution (500 ng/10 μL, prepared by Takeda PharmaceuticalCompany Limited) or PBS (10 μL, negative control group) was administeredintradermally in the ear of Balb/c mice (Charles River Japan, male, 7weeks old). Twenty-four hr after administration, the ear was resectedunder isoflurane anesthesia. The test compound was suspended in 0.5%methylcellulose and administered orally 30 min before and 8 hr afterIL-23 administration.

RNA extraction from the ear tissue and quantitative PCR were performedas follows. Specifically, ear tissue 5 mm in diameter was punched froman area of the resected ear centering on the IL-23 injection site, andthe tissue was immersed in RNAlater (QIAGEN) for at least 18 hr. TheRNAlater-treated ear tissue was homogenized in 350 μL of RLT buffer(RNeasy mini kit, QIAGEN) and treated (55° C., 10 min) with Proteinase K(QIAGEN). Total RNA was then extracted according to the RNeasy mini kitprotocol. The RNA thus obtained was then reverse transcribed into cDNAusing the High-Capacity RNA-to-cDNA kit (Applied Biosystems), and theamount of each cytokine expressions was measured by real-time PCR(Viia7™, Applied Biosystems). The PCR buffer used was TaqMan FastAdvanced Master Mix (Applied Biosystems), and TaqMan Gene ExpressionAssays (Applied Biosystems) Mm00439618 m1 (IL-17A) and 4352341E(β-actin) were used for cytokine gene detection. The IL-17A geneexpression level was normalized to the β-actin gene expression level,and the percent inhibition of IL-17A gene expression with the testcompound was then calculated.

The results obtained with the above-described method (percent inhibitionof IL-17A gene expression with oral administration of the test compound)are shown in Table 3.

TABLE 3 percent inhibition of Ex. No. Dose (mg/kg) IL-17A geneexpression * 14 100 53% 23 100 71% 24 100 65% 106 100 43% * versus thenegative control group

The results above showed that oral administration of the examplecompounds inhibited IL-17A gene expression in vivo.

Experimental Example 5

Effect in a Mouse Model of IL-23-Induced Psoriasis

Mouse IL-23 (500 ng/15 μL, R&D) or PBS (15 μL, negative control group)was administered intradermally in the ear of Balb/c mice (Charles RiverJapan, male, 7 weeks old) 5 times every other days. Seven hr after IL-23administration at 8 days after the initial administration (finaladministration), the mice were anesthetized with isoflurane, and earthickness was measured with calipers. After the ear thickness wasmeasured, the ear was resected, the tissue 8 mm in diameter was punchedfrom an area centering on the IL-23 injection site, and the tissue wasweighed. The test compound was suspended in 0.5% methylcellulose andadministered orally twice daily on consecutive days from 30 min beforethe initial IL-23 administration to 30 min before the final IL-23administration.

The change in ear thickness in this model was evaluated by calculatingthe difference in measured thickness between before IL-23 administrationand 7 hr after the final IL-23 administration.

The amount of IL-17 in the ear tissue was performed as follows. The eartissue 8 mm in diameter resected above was homogenized in 500 μL ofTissue extraction Reagent I (invitrogen) containing protease inhibitor(Roche Diagnostics). The homogenized solution was centrifuged, and theamount of IL-17 in the supernatant was measured using ELISA kit (R&D),and the amount of protein in the supernatant was measured using pierceBCA protein assay kit (Thermo scientific). The amount of IL-17 in eachear tissue was normalized to the amount of protein, and the percentinhibition of IL-17A production with the test compound was thencalculated.

The measurement results obtained with the above-described method(percent inhibition of ear thickness, and percent inhibition of IL-17Aproduction with oral administration of the test compound) are shown inTable 4.

TABLE 4 Dose percent inhibition of percent inhibition of Ex. No. (mg/kg)ear thickness* IL-17 production* 24 100 76% 96% *versus the negativecontrol group

The results above showed that oral administration of the examplecompounds inhibited the increase in ear thickness, and IL-17A productionin the mouse model of psoriasis.

(1) the compound of Example 1 10.0 g (2) lactose 70.0 g (3) cornstarch50.0 g (4) soluble starch  7.0 g (5) magnesium stearate  3.0 g

The compound of Example 1 (10.0 g) and magnesium stearate (3.0 g) aregranulated in aqueous solution (70 mL) of soluble starch (7.0 g assoluble starch) and then dried, the resulting mixture is mixed withlactose (70.0 g) and cornstarch (50.0 g) (lactose, cornstarch, solublestarch and magnesium stearate are all products in compliance withJapanese Pharmacopoeia 14^(th) Edition). The mixture compressed to givetablets.

INDUSTRIAL APPLICABILITY

The compound of the present invention has a superior RORγt inhibitoryaction, and useful as an agent for the prophylaxis or treatment ofpsoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC),Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis, uveitis,asthma, ankylopoietic spondylarthritis, systemic lupus erythematosus(SLE) and the like.

This application is based on patent application No. 2013-140213 filed onJul. 3, 2013 in Japan, the contents of which are encompassed in fullherein.

The invention claimed is:
 1. A method for the treatment of inflammatorybowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD),rheumatoid arthritis, multiple sclerosis, uveitis, asthma, ankylosingspondylitis, or systemic lupus erythematosus (SLE), which comprisesadministering an effective amount of a compound represented by thefollowing formula

wherein Ring A is a benzene ring optionally further substituted by 1 to3 substituents selected from (1) a halogen atom, and (2) a cyano group;R₁ is (1) a group represented by the formula: -Q(R^(1a))(R^(1b))(R^(1c))wherein Q is a carbon atom or a silicon atom, and R^(1a), R^(1b) andR^(1c) are each independently a C₁₋₆ alkyl group, or (2) a neopentylgroup; R² is (1) a group represented by the formula:

wherein R⁵ is (A) a C₁₋₆ alkyl group optionally substituted by 1 to 3C₁₋₆ alkoxy groups, or (B) a C₁₋₆ alkoxy group, (2) a bicyclic fusedheterocyclic group selected from dihydrobenzofuryl and indazolyl, eachoptionally substituted by 1 to 3 C₁₋₆ alkyl groups, or (3) a grouprepresented by the formula -L-Z¹: wherein L is a bond; and Z¹ is (A) aC₃₋₁₀ cycloalkyl group optionally substituted by 1 to 3 halogen atoms,or (B) tetrahydropyranyl; R³ is (1) a hydrogen atom, or (2) a C₁₋₆ alkylgroup; and R⁴ is (1) a C₁₋₆ alkyl group optionally substituted by 1 to 7substituents selected from (a) a 3- to 8-membered monocyclicnon-aromatic heterocyclic group selected from dihydropyrimidinyl,dihydropyridyl, dihydropyridazinyl, imidazolidinyl, tetrahydropyranyl,morpholinyl, piperidyl and tetrahydropyrimidinyl, each optionallysubstituted by 1 to 3 substituents selected from (i) an oxo group, and(ii) a C₁₋₆ alkyl group, (b) a 5- or 6-membered monocyclic aromaticheterocyclic group optionally substituted by 1 to 3 substituentsselected from (i) a C₁₋₆ alkyl group, and (ii) a hydroxy group, (c) a 8-to 14-membered fused bicyclic aromatic heterocyclic group selected fromindazolyl and benzimidazolyl, (d) a halogen atom, (e) a hydroxy group,(f) a cyano group, (g) a carboxy group, (h) a C₁₋₆ alkylsulfonyl group,and (i) an amino group optionally mono- or di-substituted by C₁₋₆alkyl-carbonyl group(s), (2) a 3- to 8-membered monocyclic non-aromaticheterocyclic group selected from pyrrolidinyl, oxazolidinyl, azetidinyl,piperidyl and tetrahydropyranyl, each optionally substituted by 1 to 3substituents selected from (a) an oxo group, (b) a hydroxy group, (c) ahalogen atom, and (d) a C₁₋₆ alkyl-carbonyl group, (3) a 5-memberedmonocyclic aromatic heterocyclic group optionally substituted by 1 to 3hydroxy groups, (4) a C₃₋₁₀ cycloalkyl group optionally substituted by 1to 3 halogen atoms, or (5) an amino group optionally mono- ordi-substituted by C₁₋₆ alkyl group(s), provided thatα-(acetylamino)-N-[4-(1,1-dimethylethyl)phenyl]-cyclopentaneacetamide isexcluded, or a salt thereof, to a mammal.
 2. The method of claim 1,wherein the substituent that Ring A optionally further has is a fluorineatom or a chlorine atom.
 3. The method of claim 1, wherein R¹ is atert-butyl group, a neopentyl group or a trimethylsilyl group.
 4. Themethod of claim 1, wherein R² is (1) a group represented by the formula:

wherein R⁵ is an alkoxy group or an alkoxyalkyl group, (2) atetrahydro-2H-pyran-4-yl group, (3) a 4,4-difluorocyclohexyl group, (4)a 1-methyl-1H-indazol-5-yl group, or (5) a 2,3-dihydro-1-benzofuran-5-ylgroup.
 5. The method of claim 1, wherein R³ is a hydrogen atom or amethyl group.
 6. The method of claim 1, wherein the compound is(3S)—N-((1R)-2-((4-tert-Butyl-3-fluorophenyl)amino)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamideor a salt thereof.
 7. The method of claim 1, wherein the compound isN-((1R)-2-((3,5-Difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamideor a salt thereof.
 8. The method of claim 1, wherein the compound is(2R)—N-(4-tert-Butyl-3,5-difluorophenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)-2-(1-methyl-1H-indazol-5-yl)acetamideor a salt thereof.
 9. The method of claim 1, wherein the compound is(3R)—N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamideor a salt thereof.
 10. The method of claim 1, wherein the compound isselected from the group consisting of(3S)—N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide,N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide,N-(2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide,(2R)-2-(((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)amino)-N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide,(2R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((4-oxopyridazin-1(4H)-yl)acetyl)amino)acetamide,1-acetyl-N-((1R)-2-((3-fluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)piperidine-4-carboxamide,(2R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(((3-hydroxy-1,2-oxazol-5-yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide,(2R)—N-(3-fluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((4-oxopyridin-1(4H)-yl)acetyl)amino)acetamide,(2R)—N-(4-tert-butyl-3-fluorophenyl)-2-(4-(methoxymethyl)phenyl)-2-(((6-oxopyrimidin-1(6H)-yl)acetyl)amino)acetamide,(3R)—N-((1R)-2-((4-tert-butyl-3-fluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide,N-((1R)-2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3-hydroxy-N-methyl-1,2-oxazole-5-carboxamide,N-((1R)-2-((4-tert-butyl-3-chlorophenyl)amino)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)-3,3,3-trifluoro-2-hydroxypropanamide,(2R)—N-(2,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)-2-(((5-methyl-1,3,4-oxadiazol-2-yl)acetyl)amino)acetamide,and(2R)—N-(4-tert-butyl-3-fluorophenyl)-2-(((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl)amino)-2-(4-(methoxymethyl)phenyl)acetamide,or a salt thereof.
 11. The method of claim 1, wherein the compound is(3R)—N-((1R)-2-((4-tert-butyl-3-fluorophenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)-5-oxopyrrolidine-3-carboxamide.